Therapeutic inhibition of lactate dehydrogenase and agents therefor

ABSTRACT

This invention relates to compounds, compositions, and methods useful for reducing lactact dehydrogenase target RNA and protein levels via use of ds RNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/518,009, entitled “Therapeutic Inhibition of Lactate Dehydrogenaseand Agents Therefor,” filed Apr. 10, 2017 which is a national stagefiling under 35 U.S.C. § 371 of International Application Ser. No.PCT/US2015/054959, filed Oct. 9, 2015 and published in English on Apr.14, 2016 as publication WO 2016/057932 A1, which claims the benefitunder 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Ser. No.62/062,424, entitled “Methods and Compositions for the SpecificInhibition of Lactate Dehydrogenase by Double-Stranded RNA”, which wasfiled Oct. 10, 2014, and to U.S. Provisional Patent Application Ser. No.62/199,056, entitled “Therapeutic Inhibition of Lactate Dehydrogenaseand Agents Therefor”, which was filed Jul. 30, 2015. The entire contentsof the preceding patent applications are hereby incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, and methodsfor the study, diagnosis, and treatment of traits, diseases andconditions that respond to the modulation of lactate dehydrogenase geneexpression and/or activity.

SEQUENCE SUBMISSION

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is entitled“D080070007US03-SEQ-DWY”, which was created on Mar. 13, 2019, and is 1.4MB in size. The information in the electronic format of the SequenceListing is part of the present application and is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Primary hyperoxaluria Type 1 (“PH1”) is a rare autosomal recessiveinborn error of glyoxylate metabolism, caused by a deficiency of theliver-specific enzyme alanine:glyoxylate aminotransferase (also namedserine-pyruvate aminotransferase). The disorder results inoverproduction and excessive urinary excretion of oxalate, causingrecurrent urolithiasis and nephrocalcinosis. As glomerular filtrationrate declines due to progressive renal involvement, oxalate accumulatesleading to systemic oxalosis. The diagnosis is based on clinical andsonographic findings, urine oxalate assessment, enzymology and/or DNAanalysis. While early conservative treatment has aimed to maintain renalfunction, in chronic kidney disease Stages 4 and 5, the best outcomes todate have been achieved with combined liver-kidney transplantation(Cochat et al. Nephrol Dial Transplant 27: 1729-36).

PH1 is the most common form of primary hyperoxaluria and has anestimated prevalence of 1 to 3 cases per 1 million population and anincidence rate of approximately 1 case per 120,000 live births per yearin Europe (Cochat et al. Nephrol Dial Transplant 10 (Suppl 8): 3-7; vanWoerden et al. Nephrol Dial Transplant 18: 273-9). It accounts for 1 to2% of cases of pediatric end-stage renal disease (ESRD), according toregistries from Europe, the United States, and Japan (Harambat et al.Clin J Am Soc Nephrol 7: 458-65), but it appears to be more prevalent incountries in which consanguineous marriages are common (with aprevalence of 10% or higher in some North African and Middle Easternnations; Kamoun and Lakhoua Pediatr Nephrol 10: 479-82; see Cochat andRumsby N Engl J Med 369(7):649-58).

Lactate dehydrogenase (LDH) is the enzyme responsible for convertingglyoxylate to oxalate in the mitochondrial/peroxisomal glycinemetabolism pathway in the liver and pancreas. In the presence of LDH,increased production of glyoxylate (via, e.g., AGT1 mutation) drivesoxalate accumulation (see FIG. 2), which ultimately results in the PH1disease.

Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35nucleotides have been described as effective inhibitors of target geneexpression in mammalian cells (Rossi et al., U.S. Pat. No. 8,084,599 andU.S. Patent Application No. 2005/0277610). dsRNA agents of such lengthare believed to be processed by the Dicer enzyme of the RNA interference(RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA”(“DsiRNA”) agents. Additional modified structures of DsiRNA agents werepreviously described (Rossi et al., U.S. Patent Application No.2007/0265220). Effective extended forms of Dicer substrates have alsorecently been described (see, e.g., Brown, U.S. Pat. Nos. 8,349,809 and8,513,207).

Provided herein are improved nucleic acid agents that target lactatedehydrogenase. In particular, those targeting lactate dehydrogenase havebeen specifically exemplified.

BRIEF SUMMARY OF THE INVENTION

The present invention is based, at least in part, upon theidentification of lactate dehydrogenase as an attractive target forRNA-based (particularly dsRNA-based) knockdown therapies. It wassurprisingly identified herein that targeted knockdown of lactatedehydrogenase that appeared to exclude muscle tissue as a target organfor LDHA knockdown (e.g., primarily liver-targeted knockdown, e.g.,using LNP-mediated delivery and/or GalNAc dsNA conjugates), such as canbe achieved via use of dsRNAs as described herein in concert withdelivery modalities (e.g., lipid nanoparticles, GalNAc conjugates, etc.)could provide therapeutic benefit to a subject having chronic kidneydisease and/or pyruvate dehydrogenase complex deficiency. Identificationof a therapeutic effect of such modalities when used against diseases ordisorders such as chronic kidney disease, pyruvate dehydrogenase complexdeficiency, or against PH1 (see, e.g., Example 4 and FIGS. 5A to 5Gherein) and/or any other lactate dehydrogenase-associated disease ordisorder, including, e.g., PH2 (see, e.g., Example 5 and FIG. 5Hherein), PH3 and idiopathic hyperoxaluria, as well as oncology (whendelivered in a manner that tends to target liver cells while beinginefficient for muscle delivery, e.g., within a LNP—see, e.g., Example 7and FIGS. 10A to 10B herein), was noted as remarkable, at least in partbecause of the critical role of lactate dehydrogenase in glycolysis. Inparticular, elevated lactose levels are known to be highly deleteriousto cells and tissues, e.g., particularly in muscle and other tissues,and the robust levels of lactate dehydrogenase knockdown likely to beachieved using RNAi agents would therefore have been predicted to beharmful to a subject, in the absence of evidence to the contrary.However, the therapeutic potential of such approaches has now beenidentified herein, as the therapeutic modalities described herein havebeen established herein not only as effective but also well-tolerated(i.e., it has been discovered herein that robust knockdown of LDHA inliver does not produce a corresponding and potentially deleteriouselevation of lactate levels in the circulation of mice—see, e.g.,Example 8 and FIG. 11 herein).

The currently described LDHA-targeting therapies can be readilydistinguished from small molecule-based approaches to performing LDHAinhibition (refer, e.g., to Shi and Pinto PLoS ONE 9(1): e86365 forcertain small molecule inhibitors of LDHA). In particular, inhibition ofLDHA using small molecule inhibitors cannot be readily targeted tospecific organs without any impact upon other organs (e.g., withoutsignificant partitioning to muscle cells), due at least in part to thesmall sizes and partition coefficients of such small molecules.

Another disadvantage of small molecule-based approaches to inhibitingLDHA that is overcome by the oligonucleotide-based approaches of thecurrent invention is the tendency of small molecule inhibitors of LDHAalso to target other forms of LDH, for example, LDHB and/or LDHC. Suchnon-selective targeting of multiple forms of LDH can lead to more severenegative side effects in a treated individual than the trulyLDHA-specific oligonucleotide-based therapies described herein.

Targeting of LDHA, especially using small molecule inhibitors that arenot preferentially selective for LDHA relative to LDHB and/or LDHC, hasbeen previously identified as an oncology therapy; however, use ofLNP-mediated forms of oligonucleotide therapeutic delivery areidentified herein as allowing for delivery of LDHA inhibitory activityto optimal target organs and/or tumors, while largely preventinganti-LDHA activity in tissues and/or organs where LDHA knockdown mightbe highly deleterious in certain individuals (e.g., in muscle cells ofindividuals having chronic kidney disease, pyruvate dehydrogenasecomplex deficiency, PH1 and/or any other lactatedehydrogenase-associated disease or disorder, including, e.g., PH2, PH3and idiopathic hyperoxaluria, as well as certain types of cancer). Thus,LNP-mediated anti-LDHA RNAi agent delivery that tends not to deliver tomuscle cells of a subject yet delivers to other target organs(including, e.g., tumor) is also identified herein as a highlyattractive method for treating neoplasia in a subject.

In one aspect, the invention provides a method for treating a lactatedehydrogenase knockdown-treatable disease or disorder (e.g., chronickidney disease, pyruvate dehydrogenase complex deficiency, PH1, PH2, PH3and/or idiopathic hyperoxaluria) in a subject, involving administeringto a subject having such a disease or disorder an agent that reducesexpression of the LDHA gene in one or more tissues of the subject,thereby treating the disease or disorder in the subject.

In one embodiment, the subject has or is at elevated risk of chronickidney disease or pyruvate dehydrogenase complex deficiency.

In another embodiment, the agent that reduces expression of the LDHAgene is an RNAi agent, optionally a double stranded nucleic acid(“dsNA”). Optionally, the agent is an RNAi agent having a hairpin or atetraloop structure.

In certain embodiments, an agent of the invention is administered in alipid nanoparticle. In related embodiments, administration of the agentlargely targets the liver. Optionally, administration of the agentpreferentially targets a neoplasia tissue. In certain embodiments, theagent is not delivered to muscle tissue (or is delivered to muscletissue at very low levels as compared to, e.g., liver tissue).

In an additional embodiment, the one or more tissues of the subjectinclude liver.

Another aspect of the invention provides a method for treating aneoplasia in a subject in need thereof, involving administering to asubject having a neoplasia an LNP-packaged agent that reduces expressionof the LDHA gene in one or more tissues of the subject, thereby treatingthe neoplasia in the subject.

In one embodiment, the neoplasia is a hepatic tumor, e.g.,hepatocellular carcinoma.

In another embodiment, administering of the agent does not reduce LDHAgene expression in muscle tissues of the subject.

Optionally, the agent preferentially reduces LDHA gene expression ascompared to LDHB gene expression in the subject. In a relatedembodiment, LDHB gene expression is not reduced in the subject.

In certain embodiments, the agent that reduces expression of the LDHAgene is an RNAi molecule, optionally a double stranded nucleic acid(“dsNA”).

In another embodiment, the agent that reduces expression of the LDHAgene is an RNAi molecule possessing a hairpin or a tetraloop structure.

In an additional embodiment, the agent that reduces expression of theLDHA gene is an RNAi molecule or a single-stranded antisenseoligonucleotide.

In a related embodiment, the agent is a modified oligonucleotide.Optionally, the agent includes one or more of the followingmodifications: 2′-fluoro (2′-F), 2′-OMethyl (2′-OMe) and/or 2′-Methoxyethoxy (2′-MOE) sugar modifications, inverted abasic caps,deoxynucleobases, and/or bicyclic nucleobase analogs such as lockednucleic acids (including LNA) and/or ENA

In one embodiment, the agent includes an oligonucleotide of between 12and 80 or more nucleotides in length.

In certain embodiments, the agent is an RNAi agent having one of thefollowing structures:

-   -   a dsNA having a first oligonucleotide strand having a 5′        terminus and a 3′ terminus and a second oligonucleotide strand        having a 5′ terminus and a 3′ terminus, where each of the 5′        termini has a 5′ terminal nucleotide and each of the 3′ termini        has a 3′ terminal nucleotide, where the first strand is 15-30        nucleotide residues in length, where starting from the 5′        terminal nucleotide (position 1) positions 1 to 15 of the first        strand include at least 8 ribonucleotides; the second strand is        36-80 nucleotide residues in length and, starting from the 3′        terminal nucleotide, includes at least 8 ribonucleotides in the        positions paired with positions 1-15 of the first strand to form        a duplex; where at least the 3′ terminal nucleotide of the        second strand is unpaired with the first strand, and up to 6        consecutive 3′ terminal nucleotides are unpaired with the first        strand, thereby forming a 3′ single stranded overhang of 1-6        nucleotides; where the 5′ terminus of the second strand includes        from 5-64 consecutive nucleotides which are unpaired with the        first strand, thereby forming a 5-64 nucleotide single stranded        5′ overhang; where at least the first strand 5′ terminal and 3′        terminal nucleotides are base paired with nucleotides of the        second strand when the first and second strands are aligned for        maximum complementarity, thereby forming a substantially        duplexed region between the first and second strands; and the        second strand is sufficiently complementary to a target RNA        along at least 19 ribonucleotides of the second strand length to        reduce target gene expression when the double stranded nucleic        acid is introduced into a mammalian cell;    -   a dsNA having a first oligonucleotide strand having a 5′        terminus and a 3′ terminus and a second oligonucleotide strand        having a 5′ terminus and a 3′ terminus, where each of the 5′        termini has a 5′ terminal nucleotide and each of the 3′ termini        has a 3′ terminal nucleotide, where the second strand is 19-30        nucleotide residues in length, where starting from the 5′        terminal nucleotide (position 1) positions 1 to 19 of the second        strand include at least 8 ribonucleotides; the first strand is        25-80 nucleotide residues in length and includes at least 8        ribonucleotides in positions paired with positions 1-19 of the        second strand to form a duplex; where the 3′ terminal nucleotide        of the first strand is paired with the second strand, forming a        blunt end, or up to 6 consecutive 3′ terminal nucleotides are        unpaired with the second strand, thereby forming a 3′ single        stranded overhang of 1-6 nucleotides; where the 5′ terminus of        the first strand includes from 5-61 consecutive nucleotides        which are unpaired with the second strand, thereby forming a        5-61 nucleotide single stranded 5′ overhang; where at least the        second strand 5′ terminal and 3′ terminal nucleotides are base        paired with nucleotides of the first strand when the first and        second strands are aligned for maximum complementarity, thereby        forming a substantially duplexed region between the first and        second strands; and the second strand is sufficiently        complementary to a target RNA along at least 19 ribonucleotides        of the second strand length to reduce target gene expression        when the double stranded nucleic acid is introduced into a        mammalian cell; or    -   a dsNA having a first strand and a second strand, where the        first strand and the second strand form a duplex region of 19-25        nucleotides in length, where the first strand has a 3′ region        that extends beyond the first strand-second strand duplex region        and includes a nucleotide linker region, and the dsNA further        includes a discontinuity between the 3′ terminus of the first        strand and the 5′ terminus of the second strand, and the first        or second strand is sufficiently complementary to a target        lactate dehydrogenase mRNA sequence of SEQ ID NOs: 361-432 along        at least 15 nucleotides of the second strand length to reduce        lactate dehydrogenase target mRNA expression when the dsNA is        introduced into a mammalian cell.

In certain embodiments, the nucleotide linker includes a tetraloop,optionally the nucleotide linker is a tetraloop.

In some embodiments, the agent includes one or more dynamicpolyconjugate and/or GalNAc conjugate moieties.

In certain additional aspects, provided herein are nucleic acidcompositions that reduce expression of lactate dehydrogenase. Suchcompositions contain nucleic acids such as double stranded RNA(“dsRNA”), and methods for preparing them. The nucleic acids of theinvention are capable of reducing the expression of a target lactatedehydrogenase gene in a cell, either in vitro or in a mammalian subject.

In one aspect, the invention provides a nucleic acid having anoligonucleotide strand of 15-35 nucleotides in length that issufficiently complementary to a target lactate dehydrogenase mRNAsequence of SEQ ID NOs: 361-432 along at least 15 nucleotides of theoligonucleotide strand length to reduce lactate dehydrogenase targetmRNA expression when the nucleic acid is introduced into a mammaliancell. Optionally, the oligonucleotide strand is 19-35 nucleotides inlength.

In another aspect, the invention provides a nucleic acid having anoligonucleotide strand of 19-35 nucleotides in length that issufficiently complementary to a target lactate dehydrogenase mRNAsequence of SEQ ID NOs: 361-432 along at least 19 nucleotides of theoligonucleotide strand length to reduce lactate dehydrogenase targetmRNA expression when the nucleic acid is introduced into a mammaliancell.

In a further aspect, the invention provides a double stranded nucleicacid (dsNA) having first and second nucleic acid strands that includeRNA, where the first strand is 15-80 nucleotides in length and thesecond strand is 19-80 nucleotides in length and is sufficientlycomplementary to a target lactate dehydrogenase mRNA sequence of SEQ IDNOs: 361-432 along at least 15 nucleotides of the second oligonucleotidestrand length to reduce lactate dehydrogenase target mRNA expressionwhen the dsNA is introduced into a mammalian cell.

Optionally, the first strand is 15-53, 15-35, 19-53 or 19-35 nucleotidesin length. In certain embodiments, the second strand is 19-53 or 19-35nucleotides in length.

In an additional aspect, the invention provides a dsNA having first andsecond nucleic acid strands, where the first strand is 15-35 nucleotidesin length and the second strand of the dsNA is 19-35 nucleotides inlength and is sufficiently complementary to a target lactatedehydrogenase mRNA sequence of SEQ ID NOs: 361-432 along at least 19nucleotides of the second oligonucleotide strand length to reducelactate dehydrogenase target mRNA expression when the dsNA is introducedinto a mammalian cell.

In another aspect, the invention provides a dsNA having first and secondnucleic acid strands, where the first strand is 15-35 nucleotides inlength and the second strand of the dsNA is 19-35 nucleotides in lengthand is sufficiently complementary to a target lactate dehydrogenase mRNAsequence of SEQ ID NOs: 361-432 along at least 19 nucleotides of thesecond oligonucleotide strand length to reduce lactate dehydrogenasetarget mRNA expression, and where, starting from the 5′ end of thelactate dehydrogenase mRNA sequence of SEQ ID NOs: 361-432 (referred toas position 1), mammalian Ago2 cleaves the mRNA at a site betweenpositions 9 and 10 of the sequence when the dsNA is introduced into amammalian cell.

In a further aspect, the invention provides a dsNA molecule thatconsists of (a) a sense region and an antisense region, where the senseregion and the antisense region together form a duplex region consistingof 25-35 base pairs and the antisense region comprises a sequence thatis the complement of a sequence of any one (or more) of SEQ ID NOs:361-432; and (b) from zero to two 3′ overhang regions, where eachoverhang region is six or fewer nucleotides in length, and where,starting from the 5′ end of the lactate dehydrogenase mRNA sequence ofSEQ ID NOs: 361-432 (position 1), mammalian Ago2 cleaves the mRNA at asite between positions 9 and 10 of the sequence when the dsNA isintroduced into a mammalian cell.

In an additional aspect, the invention provides a dsNA having first andsecond nucleic acid strands and a duplex region of at least 25 basepairs, where the first strand is 25-34 nucleotides in length and thesecond strand of the dsNA is 26-35 nucleotides in length and includes1-5 single-stranded nucleotides at its 3′ terminus, where the secondoligonucleotide strand is sufficiently complementary to a target lactatedehydrogenase mRNA sequence of SEQ ID NOs: 361-432 along at least 19nucleotides of the second oligonucleotide strand length to reducelactate dehydrogenase target gene expression when the dsNA is introducedinto a mammalian cell.

In another aspect, the invention provides a dsNA having first and secondnucleic acid strands and a duplex region of at least 25 base pairs,where the first strand is 25-34 nucleotides in length and the secondstrand of the dsNA is 26-35 nucleotides in length and comprises 1-5single-stranded nucleotides at its 3′ terminus, where the 3′ terminus ofthe first oligonucleotide strand and the 5′ terminus of the secondoligonucleotide strand form a blunt end, and the second oligonucleotidestrand is sufficiently complementary to a target lactate dehydrogenasesequence of SEQ ID NOs: 361-432 or 5109-7122 along at least 19nucleotides of the second oligonucleotide strand length to reducelactate dehydrogenase mRNA expression when the dsNA is introduced into amammalian cell.

In an additional aspect, the invention provides a nucleic acidpossessing an oligonucleotide strand of 15-35 nucleotides in length,where the oligonucleotide strand is hybridizable to a target lactatedehydrogenase mRNA sequence of SEQ ID NOs: 361-432 along at least 15nucleotides of the oligonucleotide strand length.

Another aspect of the invention provides a dsNA having first and secondnucleic acid strands that include RNA, where the first strand is 15-35nucleotides in length and the second strand of the dsNA is 19-35nucleotides in length, where the second oligonucleotide strand ishybridizable to a target lactate dehydrogenase mRNA sequence of SEQ IDNOs: 361-432 along at least 15 nucleotides of the second oligonucleotidestrand length.

Other aspects of the invention provide a dsNA that is:

a dsNA comprising a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where the first strand is 25 to 53nucleotide residues in length, where starting from the first nucleotide(position 1) at the 5′ terminus of the first strand, positions 1 to 23of the first strand are ribonucleotides or modified ribonucleotides; thesecond strand is 27 to 53 nucleotide residues in length and comprises 23consecutive ribonucleotides or modified ribonucleotides that base pairwith the ribonucleotides or ribonucleotides of positions 1 to 23 of thefirst strand to form a duplex; the 5′ terminus of the first strand andthe 3′ terminus of the second strand form a blunt end, a 1-6 nucleotide5′ overhang or a 1-6 nucleotide 3′ overhang; the 3′ terminus of thefirst strand and the 5′ terminus of the second strand form a blunt end,a 1-6 nucleotide 5′ overhang or a 1-6 nucleotide 3′ overhang; at leastone of positions 24 to the 3′ terminal nucleotide residue of the firststrand is a deoxyribonucleotide or modified ribonucleotide thatoptionally base pairs with a deoxyribonucleotide of the second strand;and the second strand is sufficiently complementary to a target lactatedehydrogenase mRNA sequence selected from SEQ ID NOs: 361-432 along atleast 15 nucleotides of the second oligonucleotide strand length toreduce lactate dehydrogenase target mRNA expression when the doublestranded nucleic acid is introduced into a mammalian cell;

a dsNA comprising a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where the second strand is 27 to 53nucleotide residues in length, where starting from the first nucleotide(position 1) at the 5′ terminus of the second strand, positions 1 to 23of the second strand are ribonucleotides or modified ribonucleotides;the first strand is 25 to 53 nucleotide residues in length and comprises23 consecutive ribonucleotides or modified ribonucleotides that basepair sufficiently with the ribonucleotides of positions 1 to 23 of thesecond strand to form a duplex; at least one of positions 24 to the 3′terminal nucleotide residue of the second strand is adeoxyribonucleotide or modified ribonucleotide, optionally that basepairs with a deoxyribonucleotide or modified ribonucleotide of the firststrand; and the second strand is sufficiently complementary to a targetlactate dehydrogenase mRNA sequence selected from SEQ ID NOs: 361-432along at least 15 nucleotides of the second oligonucleotide strandlength to reduce lactate dehydrogenase target mRNA expression when thedouble stranded nucleic acid is introduced into a mammalian cell;

a dsNA comprising a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first strand (or the second strand) is 25-30nucleotide residues in length, where starting from the 5′ terminalnucleotide (position 1) positions 1 to 23 of the first strand (or thesecond strand) include at least 8 ribonucleotides; the second strand (orthe first strand) is 36-80 nucleotide residues in length and, startingfrom the 3′ terminal nucleotide, includes at least 8 ribonucleotides inthe positions paired with positions 1-23 of the first strand to form aduplex; where at least the 3′ terminal nucleotide of the second strand(or the first strand) is unpaired with the first strand (or the secondstrand), and up to 6 consecutive 3′ terminal nucleotides are unpairedwith the first strand (or the second strand), thereby forming a 3′single stranded overhang of 1-6 nucleotides; where the 5′ terminus ofthe second strand (or the first strand) includes from 10-30 consecutivenucleotides which are unpaired with the first strand (or the secondstrand), thereby forming a 10-30 nucleotide single stranded 5′ overhang;where at least the first strand (or the second strand) 5′ terminal and3′ terminal nucleotides are base paired with nucleotides of the secondstrand (or first strand) when the first and second strands are alignedfor maximum complementarity, thereby forming a substantially duplexedregion between the first and second strands; and the second strand issufficiently complementary to a target RNA along at least 19ribonucleotides of the second strand length to reduce target geneexpression when the double stranded nucleic acid is introduced into amammalian cell;

a dsNA comprising a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first strand is 25-35 nucleotide residues inlength, where starting from the 5′ terminal nucleotide (position 1)positions 1 to 25 of the second strand include at least 8ribonucleotides; the second strand is 30-80 nucleotide residues inlength and, starting from the 3′ terminal nucleotide, comprises at least8 ribonucleotides in the positions paired with positions 1-25 of thefirst strand to form a duplex; where the 5′ terminus of the secondstrand comprises from 5-35 consecutive nucleotides which are unpairedwith the first strand, thereby forming a 5-35 nucleotide single stranded5′ overhang; where at least the first strand 5′ terminal and 3′ terminalnucleotides are base paired with nucleotides of the second strand whenthe first and second strands are aligned for maximum complementarity,thereby forming a substantially duplexed region between the first andsecond strands; and the second strand is sufficiently complementary to atarget lactate dehydrogenase mRNA sequence selected from SEQ ID NOs:361-432 along at least 15 nucleotides of the second oligonucleotidestrand length to reduce lactate dehydrogenase target mRNA expressionwhen the double stranded nucleic acid is introduced into a mammaliancell;

a dsNA comprising a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the second strand is 19-30 nucleotide residues inlength and optionally 25-30 nucleotide residues in length, wherestarting from the 5′ terminal nucleotide (position 1) positions 1 to 17(optionally positions 1 to 23) of the second strand include at least 8ribonucleotides; the first strand is 24-80 nucleotide residues in length(optionally 30-80 nucleotide residues in length) and, starting from the3′ terminal nucleotide, comprises at least 8 ribonucleotides in thepositions paired with positions 1 to 17 (optionally positions 1 to 23)of the second strand to form a duplex; where the 3′ terminus of thefirst strand and the 5′ terminus of the second strand form a blunt end,a 3′ overhang or a 5′ overhang, optionally where the overhang is 1-6nucleotides in length; where the 5′ terminus of the first strandcomprises from 5-35 consecutive nucleotides which are unpaired with thesecond strand, thereby forming a 5-35 nucleotide single-stranded 5′overhang; where at least the second strand 5′ terminal and 3′ terminalnucleotides are base paired with nucleotides of the first strand whenthe first and second strands are aligned for maximum complementarity,thereby forming a substantially duplexed region between the first andsecond strands; and the second strand is sufficiently complementary to atarget lactate dehydrogenase mRNA sequence selected from SEQ ID NOs:361-432 along at least 15 nucleotides of the second oligonucleotidestrand length to reduce lactate dehydrogenase target mRNA expressionwhen the double stranded nucleic acid is introduced into a mammaliancell;

a dsNA comprising a first strand and a second strand, where the firststrand and the second strand form a duplex region of 19-25 nucleotidesin length, where the first strand comprises a 3′ region that extendsbeyond the first strand-second strand duplex region and comprises atetraloop, and the dsNA further comprises a discontinuity between the 3′terminus of the first strand and the 5′ terminus of the second strand,and the first or second strand is sufficiently complementary to a targetlactate dehydrogenase mRNA sequence selected from SEQ ID NOs: 361-432along at least 15 nucleotides of the first or second strand length toreduce lactate dehydrogenase target mRNA expression when the dsNA isintroduced into a mammalian cell; or

a dsNA comprising a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first oligonucleotide strand is 25-53 nucleotidesin length and the second is oligonucleotide strand is 25-53 nucleotidesin length, and where the dsNA is sufficiently highly modified tosubstantially prevent dicer cleavage of the dsNA, optionally where thedsNA is cleaved by non-dicer nucleases to yield one or more 19-23nucleotide strand length dsNAs capable of reducing LDH mRNA expressionin a mammalian cell.

A further aspect of the invention provides an in vivo hybridizationcomplex within a cell that includes an exogenous nucleic acid sequenceand a target Lactate Dehydrogenase mRNA sequence of SEQ ID NOs: 361-432.

An additional aspect of the invention provides an in vitro hybridizationcomplex within a cell that includes an exogenous nucleic acid sequenceand a target Lactate Dehydrogenase mRNA sequence of SEQ ID NOs: 361-432.

In one embodiment, the dsNA has a duplex region that is 19-21 basepairs, 21-25 base pairs or at least 25 base pairs in length.

In another embodiment, the second oligonucleotide strand includes 1-5single-stranded nucleotides at its 3′ terminus.

In an additional embodiment, the first strand is 25-35 nucleotides inlength. Optionally, the second strand is 25-35 nucleotides in length.

In another embodiment, the second oligonucleotide strand iscomplementary to target lactate dehydrogenase cDNA sequence GenBankAccession No. NM_005566.3 along at most 27 nucleotides of the secondoligonucleotide strand length.

In one embodiment, the dsNA or hybridization complex comprises amodified nucleotide. Optionally, the modified nucleotide residue is ofthe group consisting of 2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro,2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio,4′-CH2-O-2′-bridge, 4′-(CH2)2-O-2′-bridge, 2′-LNA, 2′-amino and2′-O-(N-methlycarbamate).

In a further embodiment, starting from the first nucleotide (position 1)at the 3′ terminus of the first oligonucleotide strand, position 1, 2 or3 is substituted with a modified nucleotide. Optionally, the modifiednucleotide residue of the 3′ terminus of the first strand is adeoxyribonucleotide, an acyclonucleotide or a fluorescent molecule. Incertain embodiments, position 1 of the 3′ terminus of the firstoligonucleotide strand is a deoxyribonucleotide.

In one embodiment, the first strand is 25 nucleotides in length and thesecond strand is 27 nucleotides in length. Optionally, the 3′ terminusof the first strand and the 5′ terminus of the second strand form ablunt end.

In another embodiment, starting from the 5′ end of a lactatedehydrogenase mRNA sequence of SEQ ID NOs: 361-432 (position 1),mammalian Ago2 cleaves the mRNA at a site between positions 9 and 10 ofthe sequence, thereby reducing lactate dehydrogenase target mRNAexpression when the dsNA is introduced into a mammalian cell.Optionally, the second strand includes a sequence of SEQ ID NOs: 73-144.In certain embodiments, the first strand includes a sequence of SEQ IDNOs: 1-72.

In one embodiment, the dsNA includes a pair of first strand/secondstrand sequences of Table 2.

In a further embodiment, each of the first and the second strands has alength which is at least 26 nucleotides.

In one embodiment, nucleotides of the 1-5 single-stranded nucleotides ofthe 3′ terminus of the second strand include a modified nucleotide.Optionally, the modified nucleotide is a 2′-O-methyl ribonucleotide. Ina related embodiment, all nucleotides of the 1-5 single-strandednucleotides of the 3′ terminus of the second strand are modifiednucleotides. In certain embodiments, the 1-5 single-stranded nucleotidesof the 3′ terminus of the second strand are 1-4 nucleotides in length,are 1-3 nucleotides in length, or are 1-2 nucleotides in length. In arelated embodiment, the 1-5 single-stranded nucleotides of the 3′terminus of the second strand is two nucleotides in length and includesa 2′-O-methyl modified ribonucleotide.

In one embodiment, the dsNA has a second strand possessing 5-35nucleotides at its 3′ terminus. Optionally, the single-strandednucleotides include modified nucleotides. In certain embodiments, themodified nucleotide(s) are 2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro,2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio,4′-CH2-O-2′-bridge, 4′-(CH2)2-O-2′-bridge, 2′-LNA, 2′-amino and/or2′-O-(N-methlycarbamate) modified nucleotides. In one embodiment, thesingle-stranded nucleotides include ribonucleotides. Optionally, thesingle-stranded nucleotides include deoxyribonucleotides.

In some embodiments, the agent, nucleic acid, dsNA or hybridizationcomplex of the invention also reduces mRNA expression of LDHB and/orLDHC.

In another embodiment, the nucleic acid or dsNA of the invention reducesLDHA mRNA expression but does not reduce mRNA expression of LDHB or LDHCin the subject.

In certain embodiments, the second oligonucleotide strand includes amodification pattern of AS-M1 to AS-M84, AS-M88 to AS-M96, AS-M210,AS-M1* to AS-M84*, AS-M88* to AS-M96* or AS-M210*.

Optionally, the first oligonucleotide strand includes a modificationpattern of SM1 to SM119 or SM250 to SM252.

In a further embodiment, each of the first and the second strands has alength which is at least 26 and at most 30 nucleotides.

Optionally, the dsNA is cleaved endogenously in the cell by Dicer.

In certain embodiments, a dsNA of the invention includes at least oneunlocked nucleobase analog (UNA). Optionally, the at least one UNA islocated in a 3′-overhang region, a 5′-overhang region, or both suchregions of the dsNA, optionally on the guide strand of the dsNA.

In some embodiments, a dsNA of the invention is attached to a dynamicpolyconjugate (DPC). In additional embodiments, a dsNA of the inventionis administered with a DPC, where optionally the dsNA and DPC are notattached.

In some embodiments, a dsNA of the invention is attached to a GalNAcmoiety (optionally, a tri-antennary or other multi-GalNAc moiety) and/orto cholesterol or a cholesterol targeting ligand.

In certain embodiments, the amount of the agent, nucleic acid, dsNA orhybridization complex of the invention sufficient to reduce expressionof the target gene is 1 nanomolar or less, 200 picomolar or less, 100picomolar or less, 50 picomolar or less, 20 picomolar or less, 10picomolar or less, 5 picomolar or less, 2, picomolar or less or 1picomolar or less in the environment of the cell.

In one embodiment, the agent, nucleic acid, dsNA or hybridizationcomplex possesses greater potency than a 21mer siRNA directed to theidentical at least 15 or 19 nucleotides of the target lactatedehydrogenase mRNA in reducing target lactate dehydrogenase mRNAexpression when assayed in vitro in a mammalian cell at an effectiveconcentration in the environment of a cell of 1 nanomolar or less. Incertain embodiments, knockdown efficacy and/or potency is measured at aconcentration of 1 nanomolar, 200 picomolar, 100 picomolar, 50picomolar, 20 picomolar, 10 picomolar, 5 picomolar, 2, picomolar or 1picomolar in the environment of a cell.

In another embodiment, the agent, nucleic acid, dsNA or hybridizationcomplex is sufficiently complementary to the target lactatedehydrogenase mRNA sequence to reduce lactate dehydrogenase target mRNAexpression by an amount (expressed by %) that is at least 10%, at least50%, at least 80-90%, at least 95%, at least 98%, or at least 99% whenthe agent, nucleic acid, dsNA or hybridization complex is introducedinto a mammalian cell.

In certain embodiments, the first and second strands are joined by achemical linker. Optionally, the 3′ terminus of the first strand and the5′ terminus of the second strand are joined by a chemical linker.

In one embodiment, a nucleotide of the second or first strand issubstituted with a modified nucleotide that directs the orientation ofDicer cleavage.

Optionally, the agent, nucleic acid, dsNA or hybridization complexincludes a deoxyribonucleotide, a dideoxyribonucleotide, anacyclonucleotide, a 3′-deoxyadenosine (cordycepin), a3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxyinosine (ddI), a2′,3′-dideoxy-3′-thiacytidine (3TC), a2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a monophosphate nucleotideof 3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxy-3′-thiacytidine(3TC) and a monophosphate nucleotide of2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a 4-thiouracil, a5-bromouracil, a 5-iodouracil, a 5-(3-aminoallyl)-uracil, a 2′-O-alkylribonucleotide, a 2′-O-methyl ribonucleotide, a 2′-amino ribonucleotide,a 2′-fluoro ribonucleotide, or a locked nucleic acid.

In certain embodiments, the agent, nucleic acid, dsNA or hybridizationcomplex includes a phosphate backbone modification that is aphosphonate, a phosphorothioate or a phosphotriester.

In one embodiment, the agent, nucleic acid, dsNA or hybridizationcomplex includes a morpholino nucleic acid or a peptide nucleic acid(PNA).

In another embodiment, the agent, nucleic acid, dsNA or hybridizationcomplex comprises a sequence of 15 or 19 consecutive nucleotides thatincludes four or fewer mismatched nucleotide residues when the 15 or 19consecutive nucleotides are aligned for maximum complementarity with thetarget lactate dehydrogenase mRNA sequence. Optionally, the 15 or 19consecutive nucleotides include three or fewer mismatched nucleotideresidues when the 15 or 19 consecutive nucleotides are aligned formaximum complementarity with the target lactate dehydrogenase mRNAsequence. In certain embodiments, the 15 or 19 consecutive nucleotidesinclude two or fewer mismatched nucleotide residues when the 15 or 19consecutive nucleotides are aligned for maximum complementarity with thetarget lactate dehydrogenase mRNA sequence. In related embodiments, the15 or 19 consecutive nucleotides include one mismatched nucleotideresidue when the 15 or 19 consecutive nucleotides are aligned formaximum complementarity with the target lactate dehydrogenase mRNAsequence. In additional embodiments, the 15 or 19 consecutivenucleotides are perfectly complementary to the target lactatedehydrogenase mRNA sequence when the 15 or 19 consecutive nucleotidesare aligned for maximum complementarity with the target lactatedehydrogenase mRNA sequence.

In one aspect, the invention provides a method for reducing expressionof a target lactate dehydrogenase gene in a mammalian cell involvingcontacting a mammalian cell in vitro with an agent, nucleic acid, dsNAor hybridization complex of the invention in an amount sufficient toreduce expression of a target lactate dehydrogenase mRNA in the cell.

In one embodiment, target lactate dehydrogenase mRNA expression isreduced by at least 10%, at least 50% or at least 80-90%. Optionally,lactate dehydrogenase mRNA levels are reduced by at least 90% at least 8days after the cell is contacted with the agent, nucleic acid, dsNA orhybridization complex. In certain embodiments, lactate dehydrogenasemRNA levels are reduced by at least 70% at least 10 days after the cellis contacted with the agent, nucleic acid, dsNA or hybridizationcomplex.

In one aspect, the invention provides a method for reducing expressionof a target lactate dehydrogenase mRNA in a mammal involvingadministering an agent, nucleic acid, dsNA or hybridization complex ofthe invention to a mammal in an amount sufficient to reduce expressionof a target lactate dehydrogenase mRNA in the mammal.

In certain embodiments, the agent, nucleic acid, dsNA or hybridizationcomplex is formulated in a lipid nanoparticle (LNP). In one embodiment,the agent, nucleic acid, dsNA or hybridization complex is administeredat a dosage that is 1 microgram to 5 milligrams per kilogram of themammal per day, 100 micrograms to 0.5 milligrams per kilogram, 0.001 to0.25 milligrams per kilogram, 0.01 to 20 micrograms per kilogram, 0.01to 10 micrograms per kilogram, 0.10 to 5 micrograms per kilogram, or 0.1to 2.5 micrograms per kilogram.

In certain embodiments, the agent, nucleic acid, dsNA or hybridizationcomplex possesses greater potency than 21mer siRNAs directed to theidentical at least 19 nucleotides of the target lactate dehydrogenasemRNA in reducing target lactate dehydrogenase mRNA expression whenassayed in vitro in a mammalian cell at an effective concentration inthe environment of a cell of 1 nanomolar or less. In certainembodiments, knockdown efficacy and/or potency is measured at aconcentration of 1 nanomolar, 200 picomolar, 100 picomolar, 50picomolar, 20 picomolar, 10 picomolar, 5 picomolar, 2, picomolar or 1picomolar in the environment of a cell.

In another embodiment, lactate dehydrogenase mRNA levels are reduced ina tissue of the mammal by at least 70% at least 3 days after the agent,nucleic acid, dsNA or hybridization complex is administered to themammal. Optionally, the tissue is liver tissue.

In certain embodiments, administering includes intravenous injection,intramuscular injection, intraperitoneal injection, infusion,subcutaneous injection, transdermal, aerosol, rectal, vaginal, topical,oral or inhaled delivery.

In another aspect, the invention provides a method for treating orpreventing PH1 in a subject that involves administering an agent,nucleic acid, dsNA or hybridization complex of the invention to thesubject in an amount sufficient to treat or prevent PH1 in the subject.

An additional aspect of the invention provides a method for treating orpreventing primary hyperoxaluria type 2 (PH2) in a subject involvingadministering to the subject an amount of an agent, nucleic acid, dsNAor hybridization complex of the invention in an amount sufficient totreat or prevent PH2 in the subject.

Another aspect of the invention provides a method for treating orpreventing primary hyperoxaluria type 3 (PH3) in a subject comprisingadministering to the subject an amount of an agent, nucleic acid, dsNAor hybridization complex of the invention in an amount sufficient totreat or prevent PH3 in the subject.

A further aspect of the invention provides a method for treating orpreventing idiopathic hyperoxaluria in a subject comprisingadministering to the subject an amount of an agent, nucleic acid, dsNAor hybridization complex of the invention in an amount sufficient totreat or prevent idiopathic hyperoxaluria in the subject.

Another aspect of the invention provides a method for treating orpreventing cancer in a subject comprising administering to the subjectan amount of an agent, nucleic acid, dsNA or hybridization complex ofthe invention in an amount sufficient to treat or prevent cancer in thesubject.

An additional aspect of the invention provides a method for treating orpreventing chronic kidney disease or pyruvate dehydrogenase complexdeficiency in a subject involving administering to the subject an amountof an agent, nucleic acid, dsNA or hybridization complex of theinvention in an amount sufficient to treat or prevent chronic kidneydisease or pyruvate dehydrogenase deficiency in the subject.

In one embodiment, the subject is human.

In certain embodiments, the method further involves administering aninhibitor of LDHB and/or LDHC. Optionally, the inhibitor of LDHB and/orLDHC is a dsNA (optionally a siRNA or a DsiRNA).

In a further aspect, the invention provides a formulation containing anagent, nucleic acid, dsNA or hybridization complex of the inventionpresent in an amount effective to reduce target lactate dehydrogenasemRNA levels when the agent, nucleic acid, dsNA or hybridization complexis introduced into a mammalian cell in vitro by at least 10%, at least50% or at least 80-90%.

In one embodiment, the effective amount is 1 nanomolar or less, 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, 10 picomolar or less, 5 picomolar or less, 2,picomolar or less or 1 picomolar or less in the environment of the cell.

In certain embodiments, knockdown efficacy is measured at aconcentration of 1 nanomolar, 200 picomolar, 100 picomolar, 50picomolar, 20 picomolar, 10 picomolar, 5 picomolar, 2, picomolar or 1picomolar in the environment of a cell.

In another aspect, the invention provides a formulation including theagent, nucleic acid, dsNA or hybridization complex of the inventionpresent in an amount effective to reduce target lactate dehydrogenasemRNA levels when the agent, nucleic acid, dsNA or hybridization complexis introduced into a cell of a mammalian subject by at least 10%, atleast 50% or at least 80-90%. Optionally, the effective amount is adosage of 1 microgram to 5 milligrams per kilogram of the subject perday, 100 micrograms to 0.5 milligrams per kilogram, 0.001 to 0.25milligrams per kilogram, 0.01 to 20 micrograms per kilogram, 0.01 to 10micrograms per kilogram, 0.10 to 5 micrograms per kilogram, or 0.1 to2.5 micrograms per kilogram.

In certain embodiments, the formulation includes a lipid nanoparticle.Optionally, the formulation preferentially targets liver and/orneoplasia tissues. In another embodiment, the formulation preferentiallytargets muscle cells.

In an additional aspect, the invention provides a mammalian cellcontaining an agent, nucleic acid, dsNA or hybridization complex of theinvention.

In a further aspect, the invention provides a pharmaceutical compositioncontaining an agent, nucleic acid, dsNA or hybridization complex of theinvention and a pharmaceutically acceptable carrier. In one embodiment,the pharmaceutical composition further includes an LDHB and/or LDHCinhibitor (e.g., a dsNA inhibitor of LDHB and/or LDHC).

In another aspect, the invention provides a kit that includes an agent,nucleic acid, dsNA or hybridization complex of the invention andinstructions for its use.

In an additional aspect, the invention provides a composition possessinglactate dehydrogenase inhibitory activity that consists essentially ofan agent, nucleic acid, dsNA or hybridization complex of the invention.

Another aspect of the invention provides a method of hybridizing anexogenous agent, nucleic acid, dsNA or hybridization complex to mRNA ina cell that involves introducing into the cell an exogenous agent,nucleic acid, dsNA or hybridization complex sequence and hybridizing theexogenous agent, nucleic acid, dsNA or hybridization complex to a targetLactate Dehydrogenase mRNA sequence that is a sequence of SEQ ID NOs:361-432.

A further aspect of the invention provides a method of treating anindividual with a liver or lung disease or disorder that involvesintroducing into cells of the individual an exogenous agent, nucleicacid, dsNA or hybridization complex and hybridizing the exogenous agent,nucleic acid, dsNA or hybridization complex to a target LactateDehydrogenase mRNA sequence of SEQ ID NOs: 361-432.

An additional aspect of the invention provides a method of forming an invivo hybridization complex within a cell that involves introducing intothe cell an exogenous agent, nucleic acid, dsNA or hybridization complexand hybridizing the exogenous agent, nucleic acid, dsNA or hybridizationcomplex to a target Lactate Dehydrogenase mRNA sequence of SEQ ID NOs:361-432.

A further aspect of the invention provides a method of inhibitingtranslation of a target mRNA into a protein within a cell that involvesintroducing into the cell an exogenous agent, nucleic acid, dsNA orhybridization complex and hybridizing the exogenous agent, nucleic acid,dsNA or hybridization complex to a target Lactate Dehydrogenase mRNAsequence of SEQ ID NOs: 361-432, complexing the exogenous agent, nucleicacid, dsNA or hybridization complex with RISC, and cleaving the mRNA.

In one embodiment, the exogenous agent, nucleic acid, dsNA orhybridization complex is complexed with RISC. In a related embodiment,the RISC cleaves the mRNA.

A further aspect of the invention provides a dsNA having a first strandand a second strand, where the first strand is between 32 and 80 nucleicacid residues in length and possesses a tetraloop, and a second strandof 19 to 30 nucleotides in length that anneals to the first strand toform a duplex, where the second oligonucleotide strand is sufficientlycomplementary to a target lactate dehydrogenase mRNA sequence of SEQ IDNOs: 361-432 along at least 15 nucleotides of the oligonucleotide strandlength to reduce lactate dehydrogenase target mRNA expression when thedsNA is introduced into a mammalian cell.

In one embodiment, the pairs of first strand and second strand sequencesare SEQ ID NOs: 7190 and 7191; SEQ ID NOs: 7192 and 7193; SEQ ID NOs:7196 and 7197; SEQ ID NOs: 7198 and 7199; SEQ ID NOs: 7200 and 7201; SEQID NOs: 7202 and 7203; SEQ ID NOs: 7204 and 7205; SEQ ID NOs: 7206 and7207; SEQ ID NOs: 7208 and 7209; SEQ ID NOs: 7210 and 7211; or SEQ IDNOs: 7212 and 7213.

Optionally, the dsNA is LNP-formulated and/or conjugated to GalNAc,

The invention also provides a method for treating a lactatedehydrogenase knockdown-treatable disease or disorder in a subject thatinvolves administering to a subject having a lactate dehydrogenaseknockdown-treatable disease or disorder a tetraloop-containing dsNA,where the administering reduces expression of the LDHA gene in one ormore tissues of the subject, thereby treating the lactate dehydrogenaseknockdown-treatable disease or disorder in the subject.

In one embodiment, the lactate dehydrogenase knockdown-treatable diseaseor disorder is a neoplasia, optionally a liver and/or pancreatictumor(s).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of exemplary DsiRNA agents of the inventiontargeting a site in the lactate dehydrogenase RNA referred to herein asthe “lactate dehydrogenase-1287” or “LDHA-1287” target site. UPPERcase=unmodified RNA, lower case=DNA, Bold=mismatch base pairnucleotides; arrowheads indicate projected Dicer enzyme cleavage sites;dashed line indicates sense strand (top strand) sequences correspondingto the projected Argonaute 2 (Ago2) cleavage site within the targetedlactate dehydrogenase sequence.

FIG. 2 depicts an image showing glyoxylate metabolism in human livercells. Dashed and solid lines indicate diffusion across peroxisomalmembrane and metabolism, respectively. The metabolic blocks in PH1 (AGT)and PH2 (GRHPR) are designated by the crosses. Oxalate overproductioncharacterizes both inborn errors of glyoxylate metabolism. However, inPH1, AGT deficiency causes accumulation of glyoxylate and glycolatedwith increased urinary glycolate execretion, while in PH2, GRHPRdeficiency results in L-glycericaciduria. Abbreviations: AGT,alanine:glyoxylate aminotransferase; GRHPR, glyoxylatereductase/hydroxypyruvate reductase; GO, glycolate oxidase; LDH, lactatedehydrogenase; PLP, pyridoxal phosphate.

FIGS. 3A to 3J present primary screen data showing DsiRNA-mediatedknockdown of human lactate dehydrogenase (FIGS. 3A to 3D), mouse lactatedehydrogenase (FIGS. 3E to 3H), or a composite of both human and mouselactate dehydrogenase knockdown data (FIGS. 3I and 3J), in human (HeLa)and mouse (B16-F10) cells, respectively. For each DsiRNA tested, twoindependent qPCR amplicons were assayed (in human cells, amplicons“262-396” and “1304-1419” were assayed, while in mouse cells, amplicons“384-510” and “1402-1504” were assayed).

FIGS. 4A to 4C demonstrate that LDHA-targeting DsiRNAs, as well asPRODH2- and HAO1-targeting DsiRNAs potently inhibited mRNA and proteinexpression in mouse liver, in target-specific fashion. The histogram atthe left of FIG. 4A shows that DsiRNAs LDHA-402, LDHA-723 and LDHA-370(each of which is human-mouse cross-reactive) robustly knocked down LDHAmRNA levels at 24 hours post-DsiRNA injection. The right-hand panels ofFIG. 4A show dramatically reduced levels of LDHA protein in miceadministered LDHA-402 DsiRNA, even at 14 days post-i.v. injection at 1mg/kg. FIG. 4B demonstrates the duration of the LDH knockdown effectobserved for both mRNA and protein expression (using LDHA-718-M24/M527(DP2685P:DP2692G) in 2185 LNP, 1 mg/kg, single dose, intravenousinjection). FIG. 4C shows the specificity of knockdown effects for LDHA,PRODH2 and HAO1, in both mRNA expression levels and protein levels.

FIGS. 5A through 5D show that intravenous injection of LDHA-targetingDsiRNA also reduced oxalate excretion in PH1 model mice (micepre-treated with AGXT DsiRNA to simulate PH1), as compared toPBS-injected control PH1 model mice, and even as compared to PH1 modelmice administered DsiRNA targeting oxalate metabolism pathway componentsglycolate oxidase (HAO1) or PRODH2 (proline dehydrogenase (oxidase) 2;see FIG. 6). In FIGS. 5A through 5D, mice (n=5/group) were injected onday 0 and day 14 (and on additional days as indicated in the extendedstudies presented in FIGS. 5B and 5D) with AGXT-targeting DsiRNA (upperarrows of each series), then subjected to intravenous injection of PBS(upper left), anti-PRODH2 DsiRNA (upper right), anti-HAO1 DsiRNA (lowerleft) or anti-LDHA DsiRNA (lower right), respectively, at days 3, 10, 17and 24 (and additional dates as shown for results presented in FIGS. 5Band 5D). Oxalate excretion was measured at days 0, 7 and 14 forPBS-treated PH1 model mice, while levels of oxalate excretion wereassayed in DsiRNA-treated mice at days −4, 7, 14, 21 and 28 (and atindicated extended dates in FIGS. 5B and 5D). Both PBS- and PRODH2DsiRNA-treated groups of mice were observed to exhibit dramaticallyelevated oxalate excretion levels when assayed at day 7 post-AGXT DsiRNAinjection. PRODH2 DsiRNA-treated groups of mice were also observed toexhibit further elevated oxalate excretion levels when assayed at day 21post-initial AGXT DsiRNA injection (while PBS-treated mice were onlymaintained until day 14). HAO1 DsiRNA-treated groups of mice were alsoobserved to exhibit elevated oxalate excretion levels when assayed atday 7 or day 21 post-initial AGXT DsiRNA injection, though the levels ofsuch elevations appeared to be reduced as compared to PBS-treated orPRODH2 DsiRNA-treated PH1 model mice, and ultimately appeared toconverge with anti-LDHA-treated mice at extended timepoints. Remarkably,treatment of PH1 model mice with an LDHA-targeting DsiRNA under the sameinjection schedule revealed dramatic inhibitions of oxalate elevation atboth day 7 and day 21 post-initial AGXT DsiRNA injection, as well as atextended timepoints, where assessed (e.g., FIGS. 5B and 5D). Thus,reduced levels of LDHA mRNA and protein (as demonstrated in FIGS. 4A to4C above) also translated into phenotypic effects in inhibitingelevation of oxalate excretion in PH1 model mice. FIGS. 5C and 5D showthat all DsiRNAs tested in PH1 model mice (PRODH2-, HAO1- andLDHA-targeting DsiRNAs) showed at least some inhibitory impact uponoxalate concentration (left pane of FIG. 5C); however, LDHA-targetingDsiRNA demonstrated the greatest reduction of oxalate excretion, even ascompared to HAO1-targeting DsiRNA.

FIGS. 5E to 5G show that intravenous injection of LDHA-targeting DsiRNAalso exerted a protective effect in Agxt^(−/−) mice with respect toreducing urine oxalate levels, preventing ethylene glycol-induced kidneydamage and preventing ethylene glycol-induced calcium oxalate crystals.In FIG. 5E, LDHA-718-M24/M527 (DP2685P:DP2692G) in 2185 LNP in MaleAgxt^(−/−) mice challenged with ethylene glycol (a PH1 model) wasobserved to reduce urine oxalate levels, when urine samples werecollected using metabolic cages except on day 27, which was collectedmanually, and kidneys were harvested at day 27 for calcium oxalateanalysis. In FIG. 5F, administration of LDHA DsiRNA LDHA-718-M24/M527(DP2685P:DP2692G) in 2185 LNP was observed to prevent ethyleneglycol-induced kidney damage in Agxt^(−/−) mice (0.7% EG was suppliedwith drinking water to all mice were treated with LDHA DsiRNA 1 (EarlyTreatment) or 3 weeks (Late Treatment) after EG fed). In FIG. 5G,administration of LDHA DsiRNA LDHA-718-M24/M527 (DP2685P:DP2692G) in2185 LNP was also observed to prevent ethylene glycol-induced calciumoxalate crystals in Agxt^(−/−) mice (0.7% EG was supplied with drinkingwater to all mice were treated with LDHA DsiRNA 1 (Early Treatment) or 3weeks (Late Treatment) after EG fed), where half of each kidney wasprocessed per animal, and 2 sections from each half were scored. Allcounting in FIG. 5G was performed manually, with crystals/stainingvisible at a 10× magnification counted.

FIG. 5H shows that intravenous injection of LDHA-targeting DsiRNAreduced urine oxalate levels in PH2 model mice, in contrast to HAO1- andPRODH2-targeting DsiRNAs, which did not reduce urinary oxalate levels inthe PH2 model mice.

FIG. 6 depicts another schematic overview of the oxalate metabolismpathway. Primary hyperoxaluria (PH, including PH1) has been identifiedas an autosomal recessive disorder, and LDH (encoded by LDHA in theliver) is noted as controlling the final step of oxalate production. Atleast in view of its position within the oxalate metabolism pathway,LDHA is identified as a promising therapeutic target for all types ofPH.

FIGS. 7A to 7C show modification patterns and tetraloop extensions usedin synthesizing tetraloop-extended versions of LDHA-targeting DsiRNAsLDHA-718, LDHA-723 and LDHA-1360, as well as results obtained in testingsuch constructs for efficacy. “Ps” indicates a phosphorothioate linkage,while “p” indicates a terminal phosphate (with an arrow indicating theterminal residue of the second oligonucleotide strand (thenon-tetraloop-possessing strand). In FIG. 7A, the M575/M492, M576/M491and M582/M492 modification patterns present SEQ ID Nos: 7187(tetraloop-possessing first strand sequence) and 7188 (second strand),with varying modification patterns across such sequences, as indicated.The M583/M494 structure in FIG. 7A presents SEQ ID Nos: 7187(tetraloop-possessing first strand sequence) and 7189 (second strand,contains deoxynucleotides, where indicated). FIG. 7B shows histograms of% LDHA knockdown across various forms of modified tetraloop constructs,as indicated. FIG. 7C presents dose-response curves and IC₅₀ values forindicated modified forms of tetraloop-possessing constructsLDHA-723-M576/M491 (tetraloop-containing strand sequence is SEQ ID NO:7190 and guide/antisense (lower) strand is SEQ ID NO: 7191),LDHA-1360-M576/M491 and LDHA-1360-M582/M492 (tetraloop-containing strandsequence for LDHA-1360 structures is SEQ ID NO: 7192 and guide/antisense(lower) strand is SEQ ID NO: 7193).

FIGS. 8A to 8J show a set of tetraloop-possessingstructures/modification patterns that were applied to the LDHA-targetingDsiRNAs, and efficacy data for such constructs. Tested pairs ofoligonucleotide sequences comprising tetraloop-containing agentsLDHA-355, LDHA-360, LDHA-361, LDHA-367, LDHA-370, LDHA-399, LDHA-402,LDHA-719 and LDHA-892 are SEQ ID NOs: 7196 and 7197; SEQ ID NOs: 7198and 7199; SEQ ID NOs: 7200 and 7201; SEQ ID NOs: 7202 and 7203; SEQ IDNOs: 7204 and 7205; SEQ ID NOs: 7206 and 7207; SEQ ID NOs: 7208 and7209; SEQ ID NOs: 7210 and 7211; and SEQ ID NOs: 7212 and 7213,respectively. FIGS. 8A to 8B show the conversion of 25/27mermodification patterns into tetraloop-possessing agents that wasperformed. Sequences of 25/27mers are represented by SEQ ID NOs: 7194and 7195, with the various modification patterns shown made to suchsequences. Tetraloop-possessing sequences in FIGS. 8A to 8J correspondto SEQ ID NOs: 7187 and 7188. FIGS. 8B to 8J show histograms ofknockdown data obtained for all indicated tetraloop agents in vitro.Certain duplex sequences were selected for scale-up and additionaltesting.

FIGS. 9A to 9C show that GalNAc-conjugated tetraloop-possessing agentsof the invention showed dramatic knockdown efficacy in vivo, and thatsuch knockdown efficacy produced reduced urine oxalate levels in treatedPH1 model mice. In FIG. 9A, the oligonucleotides of LDHA-723-M576/M491correspond to SEQ ID NOs: 7190 and 7191.

FIGS. 10A and 10B show that LNP-formulated LDHA-718-M571/M550 possessedhigh levels of anti-tumor efficacy (TGI of 78%; FIG. 10A) and alsoproduced >75% knockdown of LDHA in Hep3B tumors of treated animals, onaverage (FIG. 10B), after a single round of dosing with theLNP/LDHA-718-M571/M550 DsiRNA.

FIG. 11 shows that LNP-formulated LDHA-targeting DsiRNAs were welltolerated in vivo.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and agents that reduceand/or inhibit the expression and/or levels of LDHA in a cell, tissueand/or subject. Modes of delivery and/or LDHA inhibitory agents that arecapable of being delivered in a manner that tends not to deliver tomuscle and/or other tissue(s) in which LDHA inhibition might bedeleterious in at least certain individuals are identified and describedherein. Certain agents of the invention knock down expression of theLDHA transcript, in certain embodiments for therapeutic purpose. LDHA isidentified herein as a therapeutic target for treatment of chronickidney disease, pyruvate dehydrogenase complex deficiency, or fortreatment of PH1 and/or any other lactate dehydrogenase-associateddisease or disorder, including, e.g., PH2, PH3 and idiopathichyperoxaluria, as well as oncology. In certain embodiments, theinvention provides compositions that contain nucleic acids, for exampledouble stranded NA (“dsNA”), and methods for preparing them, that arecapable of reducing the level and/or expression of the lactatedehydrogenase gene in vivo or in vitro. In some embodiments, such dsNAmolecules are substrates of the Dicer enzyme, having double-strandedduplex regions of approximately 25 or more nucleotides in length,optionally possessing extended single-stranded 5′ overhang regions oneither the guide or passenger strand of the Dicer substrate dsNA. Incertain embodiments, a dsNA of the invention can have first and secondstrands of a duplex joined by a nucleotide linker—optionally, such alinker includes a tetraloop. In related embodiments, one of the strandsof the dsRNA contains a region of nucleotide sequence that has a lengththat ranges from 19 to 35 nucleotides that can direct the destructionand/or translational inhibition of the targeted lactate dehydrogenasetranscript. Optionally, a dsNA of the invention is modified, for examplewith 2′-O-methyl modifications and/or GalNAc moieties.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them below, unlessspecified otherwise.

The present invention features one or more DsiRNA molecules that canmodulate (e.g., inhibit) lactate dehydrogenase expression. The DsiRNAsof the invention optionally can be used in combination with modulatorsof other genes and/or gene products associated with the maintenance ordevelopment of diseases or disorders associated with lactatedehydrogenase misregulation (e.g., oxalate accumulation, PH1, chronickidney disease, pyruvate dehydrogenase complex deficiency, etc.). TheDsiRNA agents of the invention modulate lactate dehydrogenase RNAs suchas those corresponding to the cDNA sequences referred to by GenBankAccession Nos. NM_005566.3 (human lactate dehydrogenase A) andNM_001136069.2 (mouse lactate dehydrogenase A), which are referred toherein generally as “lactate dehydrogenase.”

The below description of the various aspects and embodiments of theinvention is provided with reference to exemplary lactate dehydrogenaseRNAs, generally referred to herein as lactate dehydrogenase, LDH or LDHA(for the “A” isoform most prominently targeted). However, such referenceis meant to be exemplary only and the various aspects and embodiments ofthe invention are also directed to alternate lactate dehydrogenase RNAs,such as mutant lactate dehydrogenase RNAs or additional lactatedehydrogenase splice variants. Certain aspects and embodiments are alsodirected to other genes involved in lactate dehydrogenase pathways,including genes whose misregulation acts in association with that oflactate dehydrogenase (or is affected or affects lactate dehydrogenaseregulation) to produce phenotypic effects that may be targeted fortreatment (e.g., PH1, chronic kidney disease, pyruvate dehydrogenasecomplex deficiency, etc.). See, e.g., the enzymes of FIG. 2. Suchadditional genes, including those of pathways that act in coordinationwith lactate dehydrogenase, can be targeted using dsRNA and the methodsdescribed herein for use of lactate dehydrogenase-targeting dsRNAs.Thus, the inhibition and the effects of such inhibition of the othergenes can be performed as described herein.

The term “lactate dehydrogenase” refers to nucleic acid sequencesencoding a lactate dehydrogenase protein, peptide, or polypeptide (e.g.,lactate dehydrogenase transcripts, such as the sequences of lactatedehydrogenase Genbank Accession Nos. NM_005566.3 and NM_001136069.2). Incertain embodiments, the term “lactate dehydrogenase” is also meant toinclude other lactate dehydrogenase encoding sequence, such as otherlactate dehydrogenase isoforms, mutant lactate dehydrogenase genes,splice variants of lactate dehydrogenase genes, and lactatedehydrogenase gene polymorphisms. The term “lactate dehydrogenase” isalso used to refer to the polypeptide gene product of an lactatedehydrogenase gene/transript, e.g., an lactate dehydrogenase protein,peptide, or polypeptide, such as those encoded by lactate dehydrogenaseGenbank Accession Nos. NP_005557.1 and NP_001129541.2.

As used herein, a “lactate dehydrogenase knockdown-treatable disease ordisorder” refers to a disease or disorder known in the art to beassociated with altered lactate dehydrogenase expression, level and/oractivity, or to a disease or disorder such as PH1 in which lactatedehydrogenase knockdown is known or predicted to be therapeutic orotherwise advantageous, or to PH2, PH3 or idiopathic hyperoxaluria,chronic kidney disease, pyruvate dehydrogenase complex deficiency orcancer. Notably, a “lactate dehydrogenase knockdown-treatable disease ordisorder” includes PH1, PH2, PH3, idiopathic hyperoxaluria, chronickidney disease, pyruvate dehydrogenase complex deficiency, cancer andother art recognized diseases or disorders associated with oxalateaccumulation.

An anti-lactate dehydrogenase dsRNA of the invention is deemed topossess “lactate dehydrogenase inhibitory activity” if a statisticallysignificant reduction in lactate dehydrogenase RNA (or when the lactatedehydrogenase protein is assessed, lactate dehydrogenase protein levels)is seen when an anti-lactate dehydrogenase dsRNA of the invention isadministered to a system (e.g., cell-free in vitro system), cell, tissueor organism, as compared to a selected control. The distribution ofexperimental values and the number of replicate assays performed willtend to dictate the parameters of what levels of reduction in lactatedehydrogenase RNA (either as a % or in absolute terms) is deemedstatistically significant (as assessed by standard methods ofdetermining statistical significance known in the art). However, incertain embodiments, “lactate dehydrogenase inhibitory activity” isdefined based upon a % or absolute level of reduction in the level oflactate dehydrogenase in a system, cell, tissue or organism. Forexample, in certain embodiments, a dsRNA of the invention is deemed topossess lactate dehydrogenase inhibitory activity if at least a 5%reduction or at least a 10% reduction in lactate dehydrogenase RNA isobserved in the presence of a dsRNA of the invention relative to lactatedehydrogenase levels seen for a suitable control. (For example, in vivolactate dehydrogenase levels in a tissue and/or subject can, in certainembodiments, be deemed to be inhibited by a dsRNA agent of the inventionif, e.g., a 5% or 10% reduction in lactate dehydrogenase levels isobserved relative to a control.) In certain other embodiments, a dsRNAof the invention is deemed to possess lactate dehydrogenase inhibitoryactivity if lactate dehydrogenase RNA levels are observed to be reducedby at least 15% relative to a selected control, by at least 20% relativeto a selected control, by at least 25% relative to a selected control,by at least 30% relative to a selected control, by at least 35% relativeto a selected control, by at least 40% relative to a selected control,by at least 45% relative to a selected control, by at least 50% relativeto a selected control, by at least 55% relative to a selected control,by at least 60% relative to a selected control, by at least 65% relativeto a selected control, by at least 70% relative to a selected control,by at least 75% relative to a selected control, by at least 80% relativeto a selected control, by at least 85% relative to a selected control,by at least 90% relative to a selected control, by at least 95% relativeto a selected control, by at least 96% relative to a selected control,by at least 97% relative to a selected control, by at least 98% relativeto a selected control or by at least 99% relative to a selected control.In some embodiments, complete inhibition of lactate dehydrogenase isrequired for a dsRNA to be deemed to possess lactate dehydrogenaseinhibitory activity. In certain models (e.g., cell culture), a dsRNA isdeemed to possess lactate dehydrogenase inhibitory activity if at leasta 50% reduction in lactate dehydrogenase levels is observed relative toa suitable control. In certain other embodiments, a dsRNA is deemed topossess lactate dehydrogenase inhibitory activity if at least an 80%reduction in lactate dehydrogenase levels is observed relative to asuitable control.

By way of specific example, in Example 2 below, a series of DsiRNAstargeting lactate dehydrogenase were tested for the ability to reducelactate dehydrogenase mRNA levels in human HeLa or mouse B16-F10 cellsin vitro, at 1 nM concentrations in the environment of such cells and inthe presence of a transfection agent (Lipofectamine™ RNAiMAX,Invitrogen). Within Example 2 below, lactate dehydrogenase inhibitoryactivity was ascribed to those DsiRNAs that were observed to effect atleast a 70% reduction of lactate dehydrogenase mRNA levels under theassayed conditions. It is contemplated that lactate dehydrogenaseinhibitory activity could also be attributed to a dsRNA under eithermore or less stringent conditions than those employed for Example 2below, even when the same or a similar assay and conditions areemployed. For example, in certain embodiments, a tested dsRNA of theinvention is deemed to possess lactate dehydrogenase inhibitory activityif at least a 10% reduction, at least a 20% reduction, at least a 30%reduction, at least a 40% reduction, at least a 50% reduction, at leasta 60% reduction, at least a 75% reduction, at least an 80% reduction, atleast an 85% reduction, at least a 90% reduction, or at least a 95%reduction in lactate dehydrogenase mRNA levels is observed in amammalian cell line in vitro at 1 nM dsRNA concentration or lower in theenvironment of a cell, relative to a suitable control.

Use of other endpoints for determination of whether a double strandedRNA of the invention possesses lactate dehydrogenase inhibitory activityis also contemplated. Specifically, in one embodiment, in addition to oras an alternative to assessing lactate dehydrogenase mRNA levels, theability of a tested dsRNA to reduce lactate dehydrogenase protein levels(e.g., at 48 hours after contacting a mammalian cell in vitro or invivo) is assessed, and a tested dsRNA is deemed to possess lactatedehydrogenase inhibitory activity if at least a 10% reduction, at leasta 20% reduction, at least a 30% reduction, at least a 40% reduction, atleast a 50% reduction, at least a 60% reduction, at least a 70%reduction, at least a 75% reduction, at least an 80% reduction, at leastan 85% reduction, at least a 90% reduction, or at least a 95% reductionin lactate dehydrogenase protein levels is observed in a mammalian cellcontacted with the assayed double stranded RNA in vitro or in vivo,relative to a suitable control. Additional endpoints contemplatedinclude, e.g., assessment of a phenotype associated with reduction oflactate dehydrogenase levels—e.g., reduction of oxalate accumulationand/or PH1 phenotypes and/or PH1-associated phenotypes (e.g., kidneydiseases or disorders associated with oxalate accumulation), or diseasesor disorders of other organs, e.g., muscle, associated with oxalateaccumulation.

Lactate Dehydrogenase inhibitory activity can also be evaluated overtime (duration) and over concentration ranges (potency), with assessmentof what constitutes a dsRNA possessing lactate dehydrogenase inhibitoryactivity adjusted in accordance with concentrations administered andduration of time following administration. Thus, in certain embodiments,a dsRNA of the invention is deemed to possess lactate dehydrogenaseinhibitory activity if at least a 50% reduction in lactate dehydrogenaseactivity is observed/persists at a duration of time of 2 hours, 5 hours,10 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days,9 days, 10 days or more after administration of the dsRNA to a cell ororganism. In additional embodiments, a dsRNA of the invention is deemedto be a potent lactate dehydrogenase inhibitory agent if lactatedehydrogenase inhibitory activity (e.g., in certain embodiments, atleast 50% inhibition of lactate dehydrogenase) is observed at aconcentration of 1 nM or less, 500 pM or less, 200 pM or less, 100 pM orless, 50 pM or less, 20 pM or less, 10 pM or less, 5 pM or less, 2 pM orless or even 1 pM or less in the environment of a cell, for example,within an in vitro assay for lactate dehydrogenase inhibitory activityas described herein. In certain embodiments, a potent lactatedehydrogenase inhibitory dsRNA of the invention is defined as one thatis capable of lactate dehydrogenase inhibitory activity (e.g., incertain embodiments, at least 20% reduction of lactate dehydrogenaselevels) at a formulated concentration of 10 mg/kg or less whenadministered to a subject in an effective delivery vehicle (e.g., aneffective lipid nanoparticle formulation). Preferably, a potent lactatedehydrogenase inhibitory dsRNA of the invention is defined as one thatis capable of lactate dehydrogenase inihibitory activity (e.g., incertain embodiments, at least 50% reduction of lactate dehydrogenaselevels) at a formulated concentration of 5 mg/kg or less whenadministered to a subject in an effective delivery vehicle. Morepreferably, a potent lactate dehydrogenase inhibitory dsRNA of theinvention is defined as one that is capable of lactate dehydrogenaseinihibitory activity (e.g., in certain embodiments, at least 50%reduction of lactate dehydrogenase levels) at a formulated concentrationof 5 mg/kg or less when administered to a subject in an effectivedelivery vehicle. Optionally, a potent lactate dehydrogenase inhibitorydsRNA of the invention is defined as one that is capable of lactatedehydrogenase inhibitory activity (e.g., in certain embodiments, atleast 50% reduction of lactate dehydrogenase levels) at a formulatedconcentration of 2 mg/kg or less, or even 1 mg/kg or less, whenadministered to a subject in an effective delivery vehicle. Exemplarydiscrete formulated concentrations of lactate dehydrogenase-targetingRNAi agents of the invention include about 5 mg/kg, about 2 mg/kg, about1 mg/kg, about 500 μg/kg, about 250 μg/kg, about 100 μg/kg, about 50μg/kg, about 25 μg/kg, about 10 μg/kg, about 5 μg/kg, about 2.5 μg/kg,about 1 μg/kg, about 500 ng/kg, about 250 ng/kg, about 100 ng/kg, about50 ng/kg, about 25 ng/kg, about 10 ng/kg, about 5 ng/kg, about 2.5ng/kg, about 1 ng/kg and about 500 μg/kg.

About: As used herein, the term “about” means+/−10% of the recitedvalue. Use of “about” is contemplated in reference to all ranges andvalues recited herein.

In certain embodiments, the phrase “consists essentially of” is used inreference to the anti-lactate dehydrogenase dsRNAs of the invention. Insome such embodiments, “consists essentially of” refers to a compositionthat comprises a dsRNA of the invention which possesses at least acertain level of lactate dehydrogenase inhibitory activity (e.g., atleast 50% lactate dehydrogenase inhibitory activity) and that alsocomprises one or more additional components and/or modifications that donot significantly impact the lactate dehydrogenase inhibitory activityof the dsRNA. For example, in certain embodiments, a composition“consists essentially of” a dsRNA of the invention where modificationsof the dsRNA of the invention and/or dsRNA-associated components of thecomposition do not alter the lactate dehydrogenase inhibitory activity(optionally including potency or duration of lactate dehydrogenaseinhibitory activity) by greater than 3%, greater than 5%, greater than10%, greater than 15%, greater than 20%, greater than 25%, greater than30%, greater than 35%, greater than 40%, greater than 45%, or greaterthan 50% relative to the dsRNA of the invention in isolation. In certainembodiments, a composition is deemed to consist essentially of a dsRNAof the invention even if more dramatic reduction of lactatedehydrogenase inhibitory activity (e.g., 80% reduction, 90% reduction,etc. in efficacy, duration and/or potency) occurs in the presence ofadditional components or modifications, yet where lactate dehydrogenaseinhibitory activity is not significantly elevated (e.g., observed levelsof lactate dehydrogenase inhibitory activity are within 10% thoseobserved for the dsRNA of the invention) in the presence of additionalcomponents and/or modifications.

As used herein, the term “nucleic acid” refers to deoxyribonucleotides,ribonucleotides, or modified nucleotides, and polymers thereof insingle- or double-stranded form. The term encompasses nucleic acidscontaining known nucleotide analogs or modified backbone residues orlinkages, which are synthetic, naturally occurring, and non-naturallyoccurring, which have similar binding properties as the referencenucleic acid, and which are metabolized in a manner similar to thereference nucleotides. Examples of such analogs include, withoutlimitation, phosphorothioates, phosphoramidates, methyl phosphonates,chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleicacids (PNAs) and unlocked nucleic acids (UNAs or unlocked nucleobaseanalogs; see, e.g., Jensen et al. Nucleic Acids Symposium Series 52:133-4), and derivatives thereof.

As used herein, “nucleotide” is used as recognized in the art to includethose with natural bases (standard), and modified bases well known inthe art. Such bases are generally located at the 1′ position of anucleotide sugar moiety. Nucleotides generally comprise a base, sugarand a phosphate group. The nucleotides can be unmodified or modified atthe sugar, phosphate and/or base moiety, (also referred tointerchangeably as nucleotide analogs, modified nucleotides, non-naturalnucleotides, non-standard nucleotides and other, see, e.g., Usman andMcSwiggen, supra; Eckstein, et al., International PCT Publication No. WO92/07065; Usman et al, International PCT Publication No. WO 93/15187;Uhlman & Peyman, supra, all are hereby incorporated by referenceherein). There are several examples of modified nucleic acid bases knownin the art as summarized by Limbach, et al, Nucleic Acids Res. 22:2183,1994. Some of the non-limiting examples of base modifications that canbe introduced into nucleic acid molecules include, hypoxanthine, purine,pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxybenzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl,5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g.,ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidinesor 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others(Burgin, et al., Biochemistry 35:14090, 1996; Uhlman & Peyman, supra).By “modified bases” in this aspect is meant nucleotide bases other thanadenine, guanine, cytosine and uracil at 1′ position or theirequivalents.

As used herein, “modified nucleotide” refers to a nucleotide that hasone or more modifications to the nucleoside, the nucleobase, pentosering, or phosphate group. For example, modified nucleotides excluderibonucleotides containing adenosine monophosphate, guanosinemonophosphate, uridine monophosphate, and cytidine monophosphate anddeoxyribonucleotides containing deoxyadenosine monophosphate,deoxyguanosine monophosphate, deoxythymidine monophosphate, anddeoxycytidine monophosphate. Modifications include those naturallyoccurring that result from modification by enzymes that modifynucleotides, such as methyltransferases. Modified nucleotides alsoinclude synthetic or non-naturally occurring nucleotides. Synthetic ornon-naturally occurring modifications in nucleotides include those with2′ modifications, e.g., 2′-methoxyethoxy, 2′-fluoro, 2′-allyl,2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH₂—O-2′-bridge,4′-(CH₂)₂—O-2′-bridge, 2′-LNA or other bicyclic or “bridged” nucleosideanalog, and 2′-O-(N-methylcarbamate) or those comprising base analogs.In connection with 2′-modified nucleotides as described for the presentdisclosure, by “amino” is meant 2′-NH₂ or 2′-O—NH₂, which can bemodified or unmodified. Such modified groups are described, e.g., inEckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., U.S.Pat. No. 6,248,878. “Modified nucleotides” of the instant invention canalso include nucleotide analogs as described above.

In reference to the nucleic acid molecules of the present disclosure,modifications may exist upon these agents in patterns on one or bothstrands of the double stranded ribonucleic acid (dsRNA). As used herein,“alternating positions” refers to a pattern where every other nucleotideis a modified nucleotide or there is an unmodified nucleotide (e.g., anunmodified ribonucleotide) between every modified nucleotide over adefined length of a strand of the dsRNA (e.g., 5′-MNMNMN-3′;3′-MNMNMN-5′; where M is a modified nucleotide and N is an unmodifiednucleotide). The modification pattern starts from the first nucleotideposition at either the 5′ or 3′ terminus according to a positionnumbering convention, e.g., as described herein (in certain embodiments,position 1 is designated in reference to the terminal residue of astrand following a projected Dicer cleavage event of a DsiRNA agent ofthe invention; thus, position 1 does not always constitute a 3′ terminalor 5′ terminal residue of a pre-processed agent of the invention). Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but in certain embodiments includes at least4, 6, 8, 10, 12, 14 nucleotides containing at least 2, 3, 4, 5, 6 or 7modified nucleotides, respectively. As used herein, “alternating pairsof positions” refers to a pattern where two consecutive modifiednucleotides are separated by two consecutive unmodified nucleotides overa defined length of a strand of the dsRNA (e.g., 5′-MMNNMMNNMMNN-3′;3′-MMNNMMNNMMNN-5′; where M is a modified nucleotide and N is anunmodified nucleotide). The modification pattern starts from the firstnucleotide position at either the 5′ or 3′ terminus according to aposition numbering convention such as those described herein. Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but preferably includes at least 8, 12, 16,20, 24, 28 nucleotides containing at least 4, 6, 8, 10, 12 or 14modified nucleotides, respectively. It is emphasized that the abovemodification patterns are exemplary and are not intended as limitationson the scope of the invention.

As used herein, “base analog” refers to a heterocyclic moiety which islocated at the 1′ position of a nucleotide sugar moiety in a modifiednucleotide that can be incorporated into a nucleic acid duplex (or theequivalent position in a nucleotide sugar moiety substitution that canbe incorporated into a nucleic acid duplex). In the dsRNAs of theinvention, a base analog is generally either a purine or pyrimidine baseexcluding the common bases guanine (G), cytosine (C), adenine (A),thymine (T), and uracil (U). Base analogs can duplex with other bases orbase analogs in dsRNAs. Base analogs include those useful in thecompounds and methods of the invention., e.g., those disclosed in U.S.Pat. Nos. 5,432,272 and 6,001,983 to Benner and US Patent PublicationNo. 20080213891 to Manoharan, which are herein incorporated byreference. Non-limiting examples of bases include hypoxanthine (I),xanthine (X), 3β-D-ribofuranosyl-(2,6-diaminopyrimidine) (K),3-β-D-ribofuranosyl-(1-methyl-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione)(P), iso-cytosine (iso-C), iso-guanine (iso-G),1-β-D-ribofuranosyl-(5-nitroindole),1-β-D-ribofuranosyl-(3-nitropyrrole), 5-bromouracil, 2-aminopurine,4-thio-dT, 7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) andpyrrole-2-carbaldehyde (Pa), 2-amino-6-(2-thienyl)purine (S),2-oxopyridine (Y), difluorotolyl, 4-fluoro-6-methylbenzimidazole,4-methylbenzimidazole, 3-methyl isocarbostyrilyl, 5-methylisocarbostyrilyl, and 3-methyl-7-propynyl isocarbostyrilyl,7-azaindolyl, 6-methyl-7-azaindolyl, imidizopyridinyl,9-methyl-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyrilyl,7-propynyl isocarbostyrilyl, propynyl-7-azaindolyl,2,4,5-trimethylphenyl, 4-methylindolyl, 4,6-dimethylindolyl, phenyl,napthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenzyl,tetracenyl, pentacenyl, and structural derivates thereof (Schweitzer etal., J. Org. Chem., 59:7238-7242 (1994); Berger et al., Nucleic AcidsResearch, 28(15):2911-2914 (2000); Moran et al., J. Am. Chem. Soc.,119:2056-2057 (1997); Morales et al., J. Am. Chem. Soc., 121:2323-2324(1999); Guckian et al., J. Am. Chem. Soc., 118:8182-8183 (1996); Moraleset al., J. Am. Chem. Soc., 122(6):1001-1007 (2000); McMinn et al., J.Am. Chem. Soc., 121:11585-11586 (1999); Guckian et al., J. Org. Chem.,63:9652-9656 (1998); Moran et al., Proc. Natl. Acad. Sci.,94:10506-10511 (1997); Das et al., J. Chem. Soc., Perkin Trans.,1:197-206 (2002); Shibata et al., J. Chem. Soc., Perkin Trans., 1:1605-1611 (2001); Wu et al., J. Am. Chem. Soc., 122(32):7621-7632(2000); O'Neill et al., J. Org. Chem., 67:5869-5875 (2002); Chaudhuri etal., J. Am. Chem. Soc., 117:10434-10442 (1995); and U.S. Pat. No.6,218,108.). Base analogs may also be a universal base.

As used herein, “universal base” refers to a heterocyclic moiety locatedat the 1′ position of a nucleotide sugar moiety in a modifiednucleotide, or the equivalent position in a nucleotide sugar moietysubstitution, that, when present in a nucleic acid duplex, can bepositioned opposite more than one type of base without altering thedouble helical structure (e.g., the structure of the phosphatebackbone). Additionally, the universal base does not destroy the abilityof the single stranded nucleic acid in which it resides to duplex to atarget nucleic acid. The ability of a single stranded nucleic acidcontaining a universal base to duplex a target nucleic can be assayed bymethods apparent to one in the art (e.g., UV absorbance, circulardichroism, gel shift, single stranded nuclease sensitivity, etc.).Additionally, conditions under which duplex formation is observed may bevaried to determine duplex stability or formation, e.g., temperature, asmelting temperature (Tm) correlates with the stability of nucleic acidduplexes. Compared to a reference single stranded nucleic acid that isexactly complementary to a target nucleic acid, the single strandednucleic acid containing a universal base forms a duplex with the targetnucleic acid that has a lower Tm than a duplex formed with thecomplementary nucleic acid. However, compared to a reference singlestranded nucleic acid in which the universal base has been replaced witha base to generate a single mismatch, the single stranded nucleic acidcontaining the universal base forms a duplex with the target nucleicacid that has a higher Tm than a duplex formed with the nucleic acidhaving the mismatched base.

Some universal bases are capable of base pairing by forming hydrogenbonds between the universal base and all of the bases guanine (G),cytosine (C), adenine (A), thymine (T), and uracil (U) under base pairforming conditions. A universal base is not a base that forms a basepair with only one single complementary base. In a duplex, a universalbase may form no hydrogen bonds, one hydrogen bond, or more than onehydrogen bond with each of G, C, A, T, and U opposite to it on theopposite strand of a duplex. Preferably, the universal bases does notinteract with the base opposite to it on the opposite strand of aduplex. In a duplex, base pairing between a universal base occurswithout altering the double helical structure of the phosphate backbone.A universal base may also interact with bases in adjacent nucleotides onthe same nucleic acid strand by stacking interactions. Such stackinginteractions stabilize the duplex, especially in situations where theuniversal base does not form any hydrogen bonds with the base positionedopposite to it on the opposite strand of the duplex. Non-limitingexamples of universal-binding nucleotides include inosine,1-β-D-ribofuranosyl-5-nitroindole, and/or1-β-D-ribofuranosyl-3-nitropyrrole (US Pat. Appl. Publ. No. 20070254362to Quay et al.; Van Aerschot et al., An acyclic 5-nitroindazolenucleoside analogue as ambiguous nucleoside. Nucleic Acids Res. 1995Nov. 11; 23(21):4363-70; Loakes et al., 3-Nitropyrrole and 5-nitroindoleas universal bases in primers for DNA sequencing and PCR. Nucleic AcidsRes. 1995 Jul. 11; 23(13):2361-6; Loakes and Brown, 5-Nitroindole as anuniversal base analogue. Nucleic Acids Res. 1994 Oct. 11;22(20):4039-43).

As used herein, “loop” refers to a structure formed by a single strandof a nucleic acid, in which complementary regions that flank aparticular single stranded nucleotide region hybridize in a way that thesingle stranded nucleotide region between the complementary regions isexcluded from duplex formation or Watson-Crick base pairing. A loop is asingle stranded nucleotide region of any length. Examples of loopsinclude the unpaired nucleotides present in such structures as hairpins,stem loops, or extended loops.

As used herein, “extended loop” in the context of a dsRNA refers to asingle stranded loop and in addition 1, 2, 3, 4, 5, 6 or up to 20 basepairs or duplexes flanking the loop. In an extended loop, nucleotidesthat flank the loop on the 5′ side form a duplex with nucleotides thatflank the loop on the 3′ side. An extended loop may form a hairpin orstem loop.

As used herein, “tetraloop” in the context of a dsRNA refers to a loop(a single stranded region) consisting of four nucleotides that forms astable secondary structure that contributes to the stability of adjacentWatson-Crick hybridized nucleotides. Without being limited to theory, atetraloop may stabilize an adjacent Watson-Crick base pair by stackinginteractions. In addition, interactions among the four nucleotides in atetraloop include but are not limited to non-Watson-Crick base pairing,stacking interactions, hydrogen bonding, and contact interactions(Cheong et al., Nature 1990 Aug. 16; 346(6285):680-2; Heus and Pardi,Science 1991 Jul. 12; 253(5016):191-4). A tetraloop confers an increasein the melting temperature (Tm) of an adjacent duplex that is higherthan expected from a simple model loop sequence consisting of fourrandom bases. For example, a tetraloop can confer a melting temperatureof at least 55° C. in 10 mM NaHPO₄ to a hairpin comprising a duplex ofat least 2 base pairs in length. A tetraloop may containribonucleotides, deoxyribonucleotides, modified nucleotides, andcombinations thereof. Examples of RNA tetraloops include the UNCG familyof tetraloops (e.g., UUCG), the GNRA family of tetraloops (e.g., GAAA),and the CUUG tetraloop. (Woese et al., Proc Natl Acad Sci USA. 1990November; 87(21):8467-71; Antao et al., Nucleic Acids Res. 1991 Nov. 11;19(21):5901-5). Examples of DNA tetraloops include the d(GNNA) family oftetraloops (e.g., d(GTIA), the d(GNRA)) family of tetraloops, thed(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, thed(TNCG) family of tetraloops (e.g., d(TICG)). (Nakano et al.Biochemistry, 41 (48), 14281-14292, 2002.; SHINJI et al. Nippon KagakkaiKoen Yokoshu VOL. 78th; NO. 2; PAGE. 731 (2000).)

As used herein, the term “siRNA” refers to a double stranded nucleicacid in which each strand comprises RNA, RNA analog(s) or RNA and DNA.The siRNA comprises between 19 and 23 nucleotides or comprises 21nucleotides. The siRNA typically has 2 bp overhangs on the 3′ ends ofeach strand such that the duplex region in the siRNA comprises 17-21nucleotides, or 19 nucleotides. Typically, the antisense strand of thesiRNA is sufficiently complementary with the target sequence of thelactate dehydrogenase gene/RNA.

Where a first sequence is referred to as “substantially complementary”with respect to a second sequence herein, the two sequences can be fullycomplementary, or they may form one or more, but generally not more than4, 3 or 2 mismatched base pairs upon hybridization, while retaining theability to hybridize under the conditions most relevant to theirultimate application. However, where two oligonucleotides are designedto form, upon hybridization, one or more single stranded overhangs, suchoverhangs shall not be regarded as mismatches with regard to thedetermination of complementarity. For example, a dsRNA comprising oneoligonucleotide 21 nucleotides in length and another oligonucleotide 23nucleotides in length, wherein the longer oligonucleotide comprises asequence of 21 nucleotides that is fully complementary to the shorteroligonucleotide, may yet be referred to as “fully complementary” for thepurposes of the invention.

The term “double-stranded RNA” or “dsRNA”, as used herein, refers to acomplex of ribonucleic acid molecules, having a duplex structurecomprising two anti-parallel and substantially complementary, as definedabove, nucleic acid strands. The two strands forming the duplexstructure may be different portions of one larger RNA molecule, or theymay be separate RNA molecules. Where separate RNA molecules, such dsRNAare often referred to as siRNA (“short interfering RNA”) or DsiRNA(“Dicer substrate siRNAs”). Where the two strands are part of one largermolecule, and therefore are connected by an uninterrupted chain ofnucleotides between the 3′-end of one strand and the 5′ end of therespective other strand forming the duplex structure, the connecting RNAchain is referred to as a “hairpin loop”, “short hairpin RNA” or“shRNA”. Where the two strands are connected covalently by means otherthan an uninterrupted chain of nucleotides between the 3′-end of onestrand and the 5′end of the respective other strand forming the duplexstructure, the connecting structure is referred to as a “linker”. TheRNA strands may have the same or a different number of nucleotides. Themaximum number of base pairs is the number of nucleotides in theshortest strand of the dsRNA minus any overhangs that are present in theduplex. In addition to the duplex structure, a dsRNA may comprise one ormore nucleotide overhangs. In addition, as used herein, “dsRNA” mayinclude chemical modifications to ribonucleotides, internucleosidelinkages, end-groups, caps, and conjugated moieties, includingsubstantial modifications at multiple nucleotides and including alltypes of modifications disclosed herein or known in the art. Any suchmodifications, as used in a siRNA- or DsiRNA-type molecule, areencompassed by “dsRNA” for the purposes of this specification andclaims.

The phrase “duplex region” refers to the region in two complementary orsubstantially complementary oligonucleotides that form base pairs withone another, either by Watson-Crick base pairing or other manner thatallows for a duplex between oligonucleotide strands that arecomplementary or substantially complementary. For example, anoligonucleotide strand having 21 nucleotide units can base pair withanother oligonucleotide of 21 nucleotide units, yet only 19 bases oneach strand are complementary or substantially complementary, such thatthe “duplex region” consists of 19 base pairs. The remaining base pairsmay, for example, exist as 5′ and 3′ overhangs. Further, within theduplex region, 100% complementarity is not required; substantialcomplementarity is allowable within a duplex region. Substantialcomplementarity refers to complementarity between the strands such thatthey are capable of annealing under biological conditions. Techniques toempirically determine if two strands are capable of annealing underbiological conditions are well know in the art. Alternatively, twostrands can be synthesized and added together under biologicalconditions to determine if they anneal to one another.

As used herein “DsiRNAmm” refers to a DisRNA having a “mismatch tolerantregion” containing one, two, three or four mismatched base pairs of theduplex formed by the sense and antisense strands of the DsiRNA, wheresuch mismatches are positioned within the DsiRNA at a location(s) lyingbetween (and thus not including) the two terminal base pairs of eitherend of the DsiRNA. The structure and mismatch positioning of exemplaryforms of DsiRNAmm compositions are described in greater detail below.

Single-stranded nucleic acids that base pair over a number of bases aresaid to “hybridize.” Hybridization is typically determined underphysiological or biologically relevant conditions (e.g., intracellular:pH 7.2, 140 mM potassium ion; extracellular pH 7.4, 145 mM sodium ion).Hybridization conditions generally contain a monovalent cation andbiologically acceptable buffer and may or may not contain a divalentcation, complex anions, e.g. gluconate from potassium gluconate,uncharged species such as sucrose, and inert polymers to reduce theactivity of water in the sample, e.g. PEG. Such conditions includeconditions under which base pairs can form.

Hybridization is measured by the temperature required to dissociatesingle stranded nucleic acids forming a duplex, i.e., (the meltingtemperature; Tm). Hybridization conditions are also conditions underwhich base pairs can form. Various conditions of stringency can be usedto determine hybridization (see, e.g., Wahl, G. M. and S. L. Berger(1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol.152:507). Stringent temperature conditions will ordinarily includetemperatures of at least about 30° C., more preferably of at least about37° C., and most preferably of at least about 42° C. The hybridizationtemperature for hybrids anticipated to be less than 50 base pairs inlength should be 5-10° C. less than the melting temperature (Tm) of thehybrid, where Tm is determined according to the following equations. Forhybrids less than 18 base pairs in length, Tm(° C.)=2(# of A+Tbases)+4(# of G+C bases). For hybrids between 18 and 49 base pairs inlength, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (% G+C)-(600/N), where N isthe number of bases in the hybrid, and [Na+] is the concentration ofsodium ions in the hybridization buffer ([Na+] for 1×SSC=0.165 M). Forexample, a hybridization determination buffer is shown in Table 1.

TABLE 1 m.w./ To make 50 final conc. Vender Cat# Lot# Stock mL solutionNaCl 100 mM Sigma S-5150 41K8934 5M 1 mL KCl 80 mM Sigma P-9541 70K0002 74.55 0.298 g MgCl₂ 8 mM Sigma M-1028 120K8933 1M 0.4 mL sucrose 2% w/vFisher BP220-212 907105 342.3 1 g Tris-HCl 16 mM Fisher BP1757-500 124191M 0.8 mL NaH₂PO₄ 1 mM Sigma S-3193 52H-029515 120.0 0.006 g EDTA 0.02mM Sigma E-7889 110K89271 0.5M 2 μL H₂O Sigma W-4502 51K2359 to 50 mL pH= 7.0 at 20° C. adjust with HCl

Useful variations on hybridization conditions will be readily apparentto those skilled in the art. Hybridization techniques are well known tothose skilled in the art and are described, for example, in Benton andDavis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad.Sci., USA 72:3961, 1975); Ausubel et al. (Current Protocols in MolecularBiology, Wiley Interscience, New York, 2001); Berger and Kimmel(Antisense to Molecular Cloning Techniques, 1987, Academic Press, NewYork); and Sambrook et al., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, New York.

As used herein, “oligonucleotide strand” is a single stranded nucleicacid molecule. An oligonucleotide may comprise ribonucleotides,deoxyribonucleotides, modified nucleotides (e.g., nucleotides with 2′modifications, synthetic base analogs, etc.) or combinations thereof.Such modified oligonucleotides can be preferred over native formsbecause of properties such as, for example, enhanced cellular uptake andincreased stability in the presence of nucleases.

As used herein, the term “ribonucleotide” encompasses natural andsynthetic, unmodified and modified ribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between ribonucleotides in the oligonucleotide. As used herein,the term “ribonucleotide” specifically excludes a deoxyribonucleotide,which is a nucleotide possessing a single proton group at the 2′ ribosering position.

As used herein, the term “deoxyribonucleotide” encompasses natural andsynthetic, unmodified and modified deoxyribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between deoxyribonucleotide in the oligonucleotide. As usedherein, the term “deoxyribonucleotide” also includes a modifiedribonucleotide that does not permit Dicer cleavage of a dsRNA agent,e.g., a 2′-O-methyl ribonucleotide, a phosphorothioate-modifiedribonucleotide residue, etc., that does not permit Dicer cleavage tooccur at a bond of such a residue.

As used herein, the term “PS-NA” refers to a phosphorothioate-modifiednucleotide residue. The term “PS-NA” therefore encompasses bothphosphorothioate-modified ribonucleotides (“PS-RNAs”) andphosphorothioate-modified deoxyribonucleotides (“PS-DNAs”).

As used herein, “Dicer” refers to an endoribonuclease in the RNase IIIfamily that cleaves a dsRNA or dsRNA-containing molecule, e.g.,double-stranded RNA (dsRNA) or pre-microRNA (miRNA), intodouble-stranded nucleic acid fragments 19-25 nucleotides long, usuallywith a two-base overhang on the 3′ end. With respect to certain dsRNAsof the invention (e.g., “DsiRNAs”), the duplex formed by a dsRNA regionof an agent of the invention is recognized by Dicer and is a Dicersubstrate on at least one strand of the duplex. Dicer catalyzes thefirst step in the RNA interference pathway, which consequently resultsin the degradation of a target RNA. The protein sequence of human Diceris provided at the NCBI database under accession number NP 085124,hereby incorporated by reference.

Dicer “cleavage” can be determined as follows (e.g., see Collingwood etal., Oligonucleotides 18:187-200 (2008)). In a Dicer cleavage assay, RNAduplexes (100 pmol) are incubated in 20 μL of 20 mM Tris pH 8.0, 200 mMNaCl, 2.5 mM MgCl2 with or without 1 unit of recombinant human Dicer(Stratagene, La Jolla, Calif.) at 37° C. for 18-24 hours. Samples aredesalted using a Performa SR 96-well plate (Edge Biosystems,Gaithersburg, Md.). Electrospray-ionization liquid chromatography massspectroscopy (ESI-LCMS) of duplex RNAs pre- and post-treatment withDicer is done using an Oligo HTCS system (Novatia, Princeton, N.J.; Hailet al., 2004), which consists of a ThermoFinnigan TSQ7000, Xcalibur datasystem, ProMass data processing software and Paradigm MS4 HPLC (MichromBioResources, Auburn, Calif.). In this assay, Dicer cleavage occurswhere at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, oreven 100% of the Dicer substrate dsRNA, (i.e., 25-30 bp, dsRNA,preferably 26-30 bp dsRNA) is cleaved to a shorter dsRNA (e.g., 19-23 bpdsRNA, preferably, 21-23 bp dsRNA).

As used herein, “Dicer cleavage site” refers to the sites at which Dicercleaves a dsRNA (e.g., the dsRNA region of a DsiRNA agent of theinvention). Dicer contains two RNase III domains which typically cleaveboth the sense and antisense strands of a dsRNA. The average distancebetween the RNase III domains and the PAZ domain determines the lengthof the short double-stranded nucleic acid fragments it produces and thisdistance can vary (Macrae et al. (2006) Science 311: 195-8). As shown inFIG. 1, Dicer is projected to cleave certain double-stranded ribonucleicacids of the instant invention that possess an antisense strand having a2 nucleotide 3′ overhang at a site between the 21^(st) and 22^(nd)nucleotides removed from the 3′ terminus of the antisense strand, and ata corresponding site between the 21^(st) and 22^(nd) nucleotides removedfrom the 5′ terminus of the sense strand. The projected and/or prevalentDicer cleavage site(s) for dsRNA molecules distinct from those depictedin FIG. 1 may be similarly identified via art-recognized methods,including those described in Macrae et al. While the Dicer cleavageevents depicted in FIG. 1 generate 21 nucleotide siRNAs, it is notedthat Dicer cleavage of a dsRNA (e.g., DsiRNA) can result in generationof Dicer-processed siRNA lengths of 19 to 23 nucleotides in length.Indeed, in certain embodiments, a double-stranded DNA region may beincluded within a dsRNA for purpose of directing prevalent Dicerexcision of a typically non-preferred 19mer or 20mer siRNA, rather thana 21 mer.

In certain embodiments, dsRNAs of the invention are Dicer substratesiRNAs (“DsiRNAs”). DsiRNAs can possess certain advantages as comparedto inhibitory nucleic acids that are not dicer substrates(“non-DsiRNAs”). Such advantages include, but are not limited to,enhanced duration of effect of a DsiRNA relative to a non-DsiRNA, aswell as enhanced inhibitory activity of a DsiRNA as compared to anon-DsiRNA (e.g., a 19-23mer siRNA) when each inhibitory nucleic acid issuitably formulated and assessed for inhibitory activity in a mammaliancell at the same concentration (in this latter scenario, the DsiRNAwould be identified as more potent than the non-DsiRNA). Detection ofthe enhanced potency of a DsiRNA relative to a non-DsiRNA is often mostreadily achieved at a formulated concentration (e.g., transfectionconcentration of the dsRNA) that results in the DsiRNA elicitingapproximately 30-70% knockdown activity upon a target RNA (e.g., amRNA). For active DsiRNAs, such levels of knockdown activity are mostoften achieved at in vitro mammalian cell DsiRNA transfectionconcentrations of 1 nM or less of as suitably formulated, and in certaininstances are observed at DsiRNA transfection concentrations of 200 pMor less, 100 pM or less, 50 pM or less, 20 pM or less, 10 pM or less, 5pM or less, or even 1 pM or less. Indeed, due to the variability amongDsiRNAs of the precise concentration at which 30-70% knockdown of atarget RNA is observed, construction of an IC₅₀ curve via assessment ofthe inhibitory activity of DsiRNAs and non-DsiRNAs across a range ofeffective concentrations is a preferred method for detecting theenhanced potency of a DsiRNA relative to a non-DsiRNA inhibitory agent.

As used herein, “overhang” refers to unpaired nucleotides, in thecontext of a duplex having one or more free ends at the 5′ terminus or3′ terminus of a dsRNA. In certain embodiments, the overhang is a 3′ or5′ overhang on the antisense strand or sense strand. In someembodiments, the overhang is a 3′ overhang having a length of betweenone and six nucleotides, optionally one to five, one to four, one tothree, one to two, two to six, two to five, two to four, two to three,three to six, three to five, three to four, four to six, four to five,five to six nucleotides, or one, two, three, four, five or sixnucleotides. “Blunt” or “blunt end” means that there are no unpairednucleotides at that end of the dsRNA, i.e., no nucleotide overhang. Forclarity, chemical caps or non-nucleotide chemical moieties conjugated tothe 3′ end or 5′ end of an siRNA are not considered in determiningwhether an siRNA has an overhang or is blunt ended. In certainembodiments, the invention provides a dsRNA molecule for inhibiting theexpression of the lactate dehydrogenase target gene in a cell or mammal,wherein the dsRNA comprises an antisense strand comprising a region ofcomplementarity which is complementary to at least a part of an mRNAformed in the expression of the lactate dehydrogenase target gene, andwherein the region of complementarity is less than 35 nucleotides inlength, optionally 19-24 nucleotides in length or 25-30 nucleotides inlength, and wherein the dsRNA, upon contact with a cell expressing thelactate dehydrogenase target gene, inhibits the expression of thelactate dehydrogenase target gene by at least 10%, 25%, or 40%.

As used herein, the term “RNA processing” refers to processingactivities performed by components of the siRNA, miRNA or RNase Hpathways (e.g., Drosha, Dicer, Argonaute2 or other RISCendoribonucleases, and RNaseH), which are described in greater detailbelow (see “RNA Processing” section below). The term is explicitlydistinguished from the post-transcriptional processes of 5′ capping ofRNA and degradation of RNA via non-RISC- or non-RNase H-mediatedprocesses. Such “degradation” of an RNA can take several forms, e.g.deadenylation (removal of a 3′ poly(A) tail), and/or nuclease digestionof part or all of the body of the RNA by one or more of several endo- orexo-nucleases (e.g., RNase III, RNase P, RNase TI, RNase A (1, 2, 3,4/5), oligonucleotidase, etc.).

By “homologous sequence” is meant a nucleotide sequence that is sharedby one or more polynucleotide sequences, such as genes, gene transcriptsand/or non-coding polynucleotides. For example, a homologous sequencecan be a nucleotide sequence that is shared by two or more genesencoding related but different proteins, such as different members of agene family, different protein epitopes, different protein isoforms orcompletely divergent genes, such as a cytokine and its correspondingreceptors. A homologous sequence can be a nucleotide sequence that isshared by two or more non-coding polynucleotides, such as noncoding DNAor RNA, regulatory sequences, introns, and sites of transcriptionalcontrol or regulation. Homologous sequences can also include conservedsequence regions shared by more than one polynucleotide sequence.Homology does not need to be perfect homology (e.g., 100%), as partiallyhomologous sequences are also contemplated by the instant invention(e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%,86%, 85%, 84%, 83%, 82%, 81%, 80% etc.). Indeed, design and use of thedsRNA agents of the instant invention contemplates the possibility ofusing such dsRNA agents not only against target RNAs of lactatedehydrogenase possessing perfect complementarity with the presentlydescribed dsRNA agents, but also against target lactate dehydrogenaseRNAs possessing sequences that are, e.g., only 99%, 98%, 97%, 96%, 95%,94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%,80% etc. complementary to said dsRNA agents. Similarly, it iscontemplated that the presently described dsRNA agents of the instantinvention might be readily altered by the skilled artisan to enhance theextent of complementarity between said dsRNA agents and a target lactatedehydrogenase RNA, e.g., of a specific allelic variant of lactatedehydrogenase (e.g., an allele of enhanced therapeutic interest).Indeed, dsRNA agent sequences with insertions, deletions, and singlepoint mutations relative to the target lactate dehydrogenase sequencecan also be effective for inhibition. Alternatively, dsRNA agentsequences with nucleotide analog substitutions or insertions can beeffective for inhibition.

Sequence identity may be determined by sequence comparison and alignmentalgorithms known in the art. To determine the percent identity of twonucleic acid sequences (or of two amino acid sequences), the sequencesare aligned for comparison purposes (e.g., gaps can be introduced in thefirst sequence or second sequence for optimal alignment). Thenucleotides (or amino acid residues) at corresponding nucleotide (oramino acid) positions are then compared. When a position in the firstsequence is occupied by the same residue as the corresponding positionin the second sequence, then the molecules are identical at thatposition. The percent identity between the two sequences is a functionof the number of identical positions shared by the sequences (i.e., %homology-# of identical positions/total#of positions×100), optionallypenalizing the score for the number of gaps introduced and/or length ofgaps introduced.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In one embodiment, the alignment generated over a certainportion of the sequence aligned having sufficient identity but not overportions having low degree of identity (i.e., a local alignment). Apreferred, non-limiting example of a local alignment algorithm utilizedfor the comparison of sequences is the algorithm of Karlin and Altschul(1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin andAltschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithmis incorporated into the BLAST programs (version 2.0) of Altschul, etal. (1990) J. Mol. Biol. 215:403-10.

In another embodiment, a gapped alignment, the alignment is optimized byintroducing appropriate gaps, and percent identity is determined overthe length of the aligned sequences (i.e., a gapped alignment). Toobtain gapped alignments for comparison purposes, Gapped BLAST can beutilized as described in Altschul et al., (1997) Nucleic Acids Res.25(17):3389-3402. In another embodiment, a global alignment thealignment is optimized by introducing appropriate gaps, and percentidentity is determined over the entire length of the sequences aligned.(i.e., a global alignment). A preferred, non-limiting example of amathematical algorithm utilized for the global comparison of sequencesis the algorithm of Myers and Miller, CABIOS (1989). Such an algorithmis incorporated into the ALIGN program (version 2.0) which is part ofthe GCG sequence alignment software package. When utilizing the ALIGNprogram for comparing amino acid sequences, a PAM120 weight residuetable, a gap length penalty of 12, and a gap penalty of 4 can be used.

Greater than 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% oreven 100% sequence identity, between the dsRNA antisense strand and theportion of the lactate dehydrogenase RNA sequence is preferred.Alternatively, the dsRNA may be defined functionally as a nucleotidesequence (or oligonucleotide sequence) that is capable of hybridizingwith a portion of the lactate dehydrogenase RNA (e.g., 400 mM NaCl, 40mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. hybridization for 12-16hours; followed by washing). Additional preferred hybridizationconditions include hybridization at 70° C. in 1×SSC or 50° C. in 1×SSC,50% formamide followed by washing at 70° C. in 0.3×SSC or hybridizationat 70° C. in 4×SSC or 50° C. in 4×SSC, 50% formamide followed by washingat 67° C. in 1×SSC. The hybridization temperature for hybridsanticipated to be less than 50 base pairs in length should be 5-10° C.less than the melting temperature (Tm) of the hybrid, where Tm isdetermined according to the following equations. For hybrids less than18 base pairs in length, Tm(° C.)=2(# of A+T bases)+4(# of G+C bases).For hybrids between 18 and 49 base pairs in length, Tm(°C.)=81.5+16.6(log 10[Na+])+0.41 (% G+C)-(600/N), where N is the numberof bases in the hybrid, and [Na+] is the concentration of sodium ions inthe hybridization buffer ([Na+] for 1×SSC=0.165 M). Additional examplesof stringency conditions for polynucleotide hybridization are providedin Sambrook, J., E. F. Fritsch, and T. Maniatis, 1989, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., chapters 9 and 11, and Current Protocols inMolecular Biology, 1995, F. M. Ausubel et al., eds., John Wiley & Sons,Inc., sections 2.10 and 6.3-6.4. The length of the identical nucleotidesequences may be at least 10, 12, 15, 17, 20, 22, 25, 27 or 30 bases.

By “conserved sequence region” is meant, a nucleotide sequence of one ormore regions in a polynucleotide does not vary significantly betweengenerations or from one biological system, subject, or organism toanother biological system, subject, or organism. The polynucleotide caninclude both coding and non-coding DNA and RNA.

By “sense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to an antisense region of the dsRNA molecule. Inaddition, the sense region of a dsRNA molecule can comprise a nucleicacid sequence having homology with a target nucleic acid sequence.

In certain embodiments, an agent of the invention is an “antisensecompound” or “antisense oligomeric compound”, which refers to anoligomeric compound that is at least partially complementary to theregion of a target nucleic acid molecule to which it hybridizes andwhich modulates (increases or decreases) its expression. This termincludes oligonucleotides, oligonucleosides, oligonucleotide analogs,oligonucleotide mimetics, antisense compounds, antisense oligomericcompounds, and chimeric combinations of these. Consequently, while allantisense compounds can be said to be oligomeric compounds, not alloligomeric compounds are antisense compounds. An “antisenseoligonucleotide” is an antisense compound that is a nucleic acid-basedoligomer. An antisense oligonucleotide can, in some cases, include oneor more chemical modifications to the sugar, base, and/orinternucleoside linkages. Nonlimiting examples of antisense compoundsinclude primers, probes, antisense compounds, antisenseoligonucleotides, external guide sequence (EGS) oligonucleotides,alternate splicers, and siRNAs. As such, these compounds can beintroduced in the form of single-stranded, double-stranded, circular,branched or hairpins and can contain structural elements such asinternal or terminal bulges or loops. Antisense double-strandedcompounds can be two strands hybridized to form double-strandedcompounds or a single strand with sufficient self-complementarity toallow for hybridization and formation of a fully or partiallydouble-stranded compound. The compounds of the instant invention are notauto-catalytic. As used herein, “auto-catalytic” means a compound hasthe ability to promote cleavage of the target RNA in the absence ofaccessory factors, e.g. proteins.

In one embodiment of the invention, the antisense compound comprises asingle stranded oligonucleotide. In some embodiments of the inventionthe antisense compound contains chemical modifications. In a certainembodiment, the antisense compound is a single stranded, chimericoligonucleotide wherein the modifications of sugars, bases, andinternucleoside linkages are independently selected.

Exemplary antisense compounds in accordance with this invention maycomprise an antisense compound from about 12 to about 35 nucleobases ormore (i.e. from about 12 to about 35 or more linked nucleosides). Inother words, a single-stranded compound of the invention can comprisefrom about 12 to about 35 nucleobases, and a double-stranded antisensecompound of the invention (such as a siRNA, for example, as describedelsewhere herein) comprises two strands, each of which is independentlyfrom about 12 to about 35 or more nucleobases. This includesoligonucleotides 15 to 35 or more, e.g., 15 to 80 nucleobases in lengthand 16 to 35 or more nucleobases in length. Contained within theantisense compounds of the invention (whether single or double strandedand on at least one strand) are antisense portions. The “antisenseportion” is that part of the antisense compound that is designed to workby one of the aforementioned antisense mechanisms. One of ordinary skillin the art will appreciate that about 12 to about 35 nucleobasesincludes 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, or 35 nucleobases.

Antisense compounds about 12 to 35 nucleobases in length, optionallyabout 15 to 35 nucleobases in length, comprising a stretch of at leasteight (8), optionally at least 12, e.g., at least 15 consecutivenucleobases targeted to the active target regions, are considered to besuitable antisense compounds as well.

Modifications can be made to the agents, including, e.g., the antisensecompounds of the instant invention, and may include conjugate groupsattached to one of the termini, selected nucleobase positions, sugarpositions or to one or more of the internucleoside linkages. Possiblemodifications include, but are not limited to, 2′-fluoro (2′-F),2′-OMethyl (2′-OMe), 2′-Methoxy ethoxy (2′-MOE) sugar modifications,inverted abasic caps, deoxynucleobases, and bicyclic nucleobase analogssuch as locked nucleic acids (including LNA) and ENA.

By “antisense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to a target nucleic acid sequence. In addition,the antisense region of a dsRNA molecule comprises a nucleic acidsequence having complementarity to a sense region of the dsRNA molecule.

As used herein, “antisense strand” refers to a single stranded nucleicacid molecule which has a sequence complementary to that of a targetRNA. When the antisense strand contains modified nucleotides with baseanalogs, it is not necessarily complementary over its entire length, butmust at least hybridize with a target RNA.

As used herein, “sense strand” refers to a single stranded nucleic acidmolecule which has a sequence complementary to that of an antisensestrand. When the antisense strand contains modified nucleotides withbase analogs, the sense strand need not be complementary over the entirelength of the antisense strand, but must at least duplex with theantisense strand.

As used herein, “guide strand” refers to a single stranded nucleic acidmolecule of a dsRNA or dsRNA-containing molecule, which has a sequencesufficiently complementary to that of a target RNA to result in RNAinterference. After cleavage of the dsRNA or dsRNA-containing moleculeby Dicer, a fragment of the guide strand remains associated with RISC,binds a target RNA as a component of the RISC complex, and promotescleavage of a target RNA by RISC. As used herein, the guide strand doesnot necessarily refer to a continuous single stranded nucleic acid andmay comprise a discontinuity, preferably at a site that is cleaved byDicer. A guide strand is an antisense strand.

As used herein, “passenger strand” refers to an oligonucleotide strandof a dsRNA or dsRNA-containing molecule, which has a sequence that iscomplementary to that of the guide strand. As used herein, the passengerstrand does not necessarily refer to a continuous single strandednucleic acid and may comprise a discontinuity, preferably at a site thatis cleaved by Dicer. A passenger strand is a sense strand.

By “target nucleic acid” is meant a nucleic acid sequence whoseexpression, level or activity is to be modulated. The target nucleicacid can be DNA or RNA. For agents that target lactate dehydrogenase, incertain embodiments, the target nucleic acid is lactate dehydrogenaseRNA, e.g., in certain embodiments, lactate dehydrogenase mRNA. lactatedehydrogenase RNA target sites can also interchangeably be referenced bycorresponding cDNA sequences. Levels of lactate dehydrogenase may alsobe targeted via targeting of upstream effectors of lactatedehydrogenase, or the effects of modulated or misregulated lactatedehydrogenase may also be modulated by targeting of molecules downstreamof lactate dehydrogenase in the lactate dehydrogenase signallingpathway.

By “complementarity” is meant that a nucleic acid can form hydrogenbond(s) with another nucleic acid sequence by either traditionalWatson-Crick or other non-traditional types. In reference to the nucleicmolecules of the present invention, the binding free energy for anucleic acid molecule with its complementary sequence is sufficient toallow the relevant function of the nucleic acid to proceed, e.g., RNAiactivity. Determination of binding free energies for nucleic acidmolecules is well known in the art (see, e.g., Turner et al., 1987, CSHSymp. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad.Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc.109:3783-3785). A percent complementarity indicates the percentage ofcontiguous residues in a nucleic acid molecule that can form hydrogenbonds (e.g., Watson-Crick base pairing) with a second nucleic acidsequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10nucleotides in the first oligonucleotide being based paired to a secondnucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%,80%, 90%, and 100% complementary respectively). “Perfectlycomplementary” means that all the contiguous residues of a nucleic acidsequence will hydrogen bond with the same number of contiguous residuesin a second nucleic acid sequence. In one embodiment, a dsRNA moleculeof the invention comprises 19 to 30 (e.g., 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 or more) nucleotides that are complementary to oneor more target nucleic acid molecules or a portion thereof.

As used herein, a dsNA, e.g., DsiRNA or siRNA, having a sequence“sufficiently complementary” to a target RNA or cDNA sequence (e.g.,lactate dehydrogenase mRNA) means that the dsNA has a sequencesufficient to trigger the destruction of the target RNA (where a cDNAsequence is recited, the RNA sequence corresponding to the recited cDNAsequence) by the RNAi machinery (e.g., the RISC complex) or process. Forexample, a dsNA that is “sufficiently complementary” to a target RNA orcDNA sequence to trigger the destruction of the target RNA by the RNAimachinery or process can be identified as a dsNA that causes adetectable reduction in the level of the target RNA in an appropriateassay of dsNA activity (e.g., an in vitro assay as described in Example2 below), or, in further examples, a dsNA that is sufficientlycomplementary to a target RNA or cDNA sequence to trigger thedestruction of the target RNA by the RNAi machinery or process can beidentified as a dsNA that produces at least a 5%, at least a 10%, atleast a 15%, at least a 20%, at least a 25%, at least a 30%, at least a35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, atleast a 60%, at least a 65%, at least a 70%, at least a 75%, at least a80%, at least a 85%, at least a 90%, at least a 95%, at least a 98% orat least a 99% reduction in the level of the target RNA in anappropriate assay of dsNA activity. In additional examples, a dsNA thatis sufficiently complementary to a target RNA or cDNA sequence totrigger the destruction of the target RNA by the RNAi machinery orprocess can be identified based upon assessment of the duration of acertain level of inhibitory activity with respect to the target RNA orprotein levels in a cell or organism. For example, a dsNA that issufficiently complementary to a target RNA or cDNA sequence to triggerthe destruction of the target RNA by the RNAi machinery or process canbe identified as a dsNA capable of reducing target mRNA levels by atleast 20% at least 48 hours post-administration of said dsNA to a cellor organism. Preferably, a dsNA that is sufficiently complementary to atarget RNA or cDNA sequence to trigger the destruction of the target RNAby the RNAi machinery or process is identified as a dsNA capable ofreducing target mRNA levels by at least 40% at least 72 hourspost-administration of said dsNA to a cell or organism, by at least 40%at least four, five or seven days post-administration of said dsNA to acell or organism, by at least 50% at least 48 hours post-administrationof said dsNA to a cell or organism, by at least 50% at least 72 hourspost-administration of said dsNA to a cell or organism, by at least 50%at least four, five or seven days post-administration of said dsNA to acell or organism, by at least 80% at least 48 hours post-administrationof said dsNA to a cell or organism, by at least 80% at least 72 hourspost-administration of said dsNA to a cell or organism, or by at least80% at least four, five or seven days post-administration of said dsNAto a cell or organism.

In certain embodiments, a nucleic acid of the invention (e.g., a DsiRNAor siRNA) possesses a sequence “sufficiently complementary to hybridize”to a target RNA or cDNA sequence, thereby achieving an inhibitory effectupon the target RNA. Hybridization, and conditions available fordetermining whether one nucleic acid is sufficiently complementary toanother nucleic acid to allow the two sequences to hybridize, isdescribed in greater detail below.

As will be clear to one of ordinary skill in the art, “sufficientlycomplementary” (contrasted with, e.g., “100% complementary”) allows forone or more mismatches to exist between a dsNA of the invention and thetarget RNA or cDNA sequence (e.g., lactate dehydrogenase mRNA), providedthat the dsNA possesses complementarity sufficient to trigger thedestruction of the target RNA by the RNAi machinery (e.g., the RISCcomplex) or process. In certain embodiments, a “sufficientlycomplementary” dsNA of the invention can harbor one, two, three or evenfour or more mismatches between the dsNA sequence and the target RNA orcDNA sequence (e.g., in certain such embodiments, the antisense strandof the dsRNA harbors one, two, three, four, five or even six or moremismatches when aligned with the target RNA or cDNA sequence for maximumcomplementarity). Additional consideration of the preferred location ofsuch mismatches within certain dsRNAs of the instant invention isconsidered in greater detail below.

As used herein “cell” is used in its usual biological sense, and doesnot refer to an entire multicellular organism, e.g., specifically doesnot refer to a human. The cell can be present in an organism, e.g.,birds, plants and mammals such as humans, cows, sheep, apes, monkeys,swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterialcell) or eukaryotic (e.g., mammalian or plant cell). The cell can be ofsomatic or germ line origin, totipotent or pluripotent, dividing ornon-dividing. The cell can also be derived from or can comprise a gameteor embryo, a stem cell, or a fully differentiated cell. Within certainaspects, the term “cell” refers specifically to mammalian cells, such ashuman cells, that contain one or more dsRNA molecules of the presentdisclosure. In particular aspects, a cell processes dsRNAs ordsRNA-containing molecules resulting in RNA intereference of targetnucleic acids, and contains proteins and protein complexes required forRNAi, e.g., Dicer and RISC.

By “RNA” is meant a molecule comprising at least one, and preferably atleast 4, 8 and 12 ribonucleotide residues. The at least 4, 8 or 12 RNAresidues may be contiguous. By “ribonucleotide” is meant a nucleotidewith a hydroxyl group at the 2′ position of a β-D-ribofuranose moiety.The terms include double-stranded RNA, single-stranded RNA, RNA such aspartially purified RNA, essentially pure RNA, synthetic RNA,recombinantly produced RNA, as well as altered RNA that differs fromnaturally occurring RNA by the addition, deletion, substitution and/oralteration of one or more nucleotides. Such alterations can includeaddition of non-nucleotide material, such as to the end(s) of the dsRNAor internally, for example at one or more nucleotides of the RNA.Nucleotides in the RNA molecules of the instant invention can alsocomprise non-standard nucleotides, such as non-naturally occurringnucleotides or chemically synthesized nucleotides or deoxynucleotides.These altered RNAs can be referred to as analogs or analogs ofnaturally-occurring RNA.

In certain embodiments, an RNAi agent (e.g., dsRNA) of the invention canbe an “isolated” RNAi agent, meaning that the RNAi agent is isolatedfrom (removed and/or purified from) a natural environment.

In some embodiments, an RNAi agent (e.g., dsRNA) of the invention can bea “synthetic” RNAi agent. The term “synthetic” or “non-natural” refersto an RNAi agent (e.g., a dsRNA of the disclosure) that (i) issynthesized using a machine or (ii) that is not derived from a cell ororganism that normally produces the RNAi agent.

By “subject” is meant an organism, which is a donor or recipient ofexplanted cells or the cells themselves. “Subject” also refers to anorganism to which the dsRNA agents of the invention can be administered.A subject can be a mammal or mammalian cells, including a human or humancells.

The phrase “pharmaceutically acceptable carrier” refers to a carrier forthe administration of a therapeutic agent. Exemplary carriers includesaline, buffered saline, dextrose, water, glycerol, ethanol, andcombinations thereof. For drugs administered orally, pharmaceuticallyacceptable carriers include, but are not limited to pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while corn starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract. The pharmaceutically acceptable carrier of thedisclosed dsRNA compositions may be micellar structures, such as aliposomes, capsids, capsoids, polymeric nanocapsules, or polymericmicrocapsules.

Polymeric nanocapsules or microcapsules facilitate transport and releaseof the encapsulated or bound dsRNA into the cell. They include polymericand monomeric materials, especially including polybutylcyanoacrylate. Asummary of materials and fabrication methods has been published (seeKreuter, 1991). The polymeric materials which are formed from monomericand/or oligomeric precursors in the polymerization/nanoparticlegeneration step, are per se known from the prior art, as are themolecular weights and molecular weight distribution of the polymericmaterial which a person skilled in the field of manufacturingnanoparticles may suitably select in accordance with the usual skill.

The term “in vitro” has its art recognized meaning, e.g., involvingpurified reagents or extracts, e.g., cell extracts. The term “in vivo”also has its art recognized meaning, e.g., involving living cells, e.g.,immortalized cells, primary cells, cell lines, and/or cells in anorganism.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent (e.g., a dsRNA agent or avector or transgene encoding same) to a patient, or application oradministration of a therapeutic agent to an isolated tissue or cell linefrom a patient, who has a disorder with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisease or disorder, or symptoms of the disease or disorder. The term“treatment” or “treating” is also used herein in the context ofadministering agents prophylactically. The term “effective dose” or“effective dosage” is defined as an amount sufficient to achieve or atleast partially achieve the desired effect. The term “therapeuticallyeffective dose” is defined as an amount sufficient to cure or at leastpartially arrest the disease and its complications in a patient alreadysuffering from the disease. The term “patient” includes human and othermammalian subjects that receive either prophylactic or therapeutictreatment.

As used herein, “neoplasia” means a disease state of a human or ananimal in which there are cells and/or tissues which proliferateabnormally. Neoplastic conditions include, but are not limited to,cancers, sarcomas, tumors, leukemias, lymphomas, and the like. Aneoplastic condition refers to the disease state associated with theneoplasia. Hepatocellular carcinoma, colon cancer (e.g., colorectalcancer), lung cancer and ovarian cancer are examples (non-limiting) of aneoplastic condition.

A “cancer” in a subject refers to the presence of cells possessingcharacteristics typical of cancer-causing cells, such as uncontrolledproliferation, immortality, metastatic potential, rapid growth andproliferation rate, and certain characteristic morphological features.Often, cancer cells will be in the form of a tumor, but such cells mayexist alone within a subject, or may be a non-tumorigenic cancer cell,such as a leukemia cell. Examples of cancer include but are not limitedto hepatic carcinoma, colon cancer, colorectal cancer, breast cancer, amelanoma, adrenal gland cancer, biliary tract cancer, bladder cancer,brain or central nervous system cancer, bronchus cancer, blastoma,carcinoma, a chondrosarcoma, cancer of the oral cavity or pharynx,cervical cancer, esophageal cancer, gastrointestinal cancer,glioblastoma, hepatoma, kidney cancer, leukemia, liver cancer, lungcancer, lymphoma, non-small cell lung cancer, osteosarcoma, ovariancancer, pancreas cancer, peripheral nervous system cancer, prostatecancer, sarcoma, salivary gland cancer, small bowel or appendix cancer,small-cell lung cancer, squamous cell cancer, stomach cancer, testiscancer, thyroid cancer, urinary bladder cancer, uterine or endometrialcancer, and vulval cancer.

As used herein, the term “tumor” means a mass of transformed cells thatare characterized by neoplastic uncontrolled cell multiplication and atleast in part, by containing angiogenic vasculature. The abnormalneoplastic cell growth is rapid and continues even after the stimulithat initiated the new growth has ceased. The term “tumor” is usedbroadly to include the tumor parenchymal cells as well as the supportingstroma, including the angiogenic blood vessels that infiltrate the tumorparenchymal cell mass. Although a tumor generally is a malignant tumor,i.e., a cancer having the ability to metastasize (i.e. a metastatictumor), a tumor also can be nonmalignant (i.e. non-metastatic tumor).Tumors are hallmarks of cancer, a neoplastic disease the natural courseof which is fatal. Cancer cells exhibit the properties of invasion andmetastasis and are highly anaplastic.

Various methodologies of the instant invention include at least one stepthat involves comparing a value, level, feature, characteristic,property, etc. to a “suitable control”, referred to interchangeablyherein as an “appropriate control”. A “suitable control” or “appropriatecontrol” is a control or standard familiar to one of ordinary skill inthe art useful for comparison purposes. In one embodiment, a “suitablecontrol” or “appropriate control” is a value, level, feature,characteristic, property, etc. determined prior to performing an RNAimethodology, as described herein. For example, a transcription rate,mRNA level, translation rate, protein level, biological activity,cellular characteristic or property, genotype, phenotype, etc. can bedetermined prior to introducing an RNA silencing agent (e.g., DsiRNA) ofthe invention into a cell or organism. In another embodiment, a“suitable control” or “appropriate control” is a value, level, feature,characteristic, property, etc. determined in a cell or organism, e.g., acontrol or normal cell or organism, exhibiting, for example, normaltraits. In yet another embodiment, a “suitable control” or “appropriatecontrol” is a predefined value, level, feature, characteristic,property, etc.

Lactate Dehydrogenase as an RNAi Target

Primary Hyperoxaluria Type 1 (PH1)

Primary hyperoxaluria results in increased excretion of oxalate, withoxalate stones being common. The oxalalate in these common conditions isderived from dietary sources or is secondary to malabsorption. Primaryhyperoxaluria, on the other hand, refers to a specific type ofhyperoxaluria that is due to a metabolic defect resulting from aheritable genetic defect. PH1 refers to the form of primaryhyperoxaluria associated with a metabolic defect of serine-pyruvateaminotransferase (an enzyme that in humans is encoded by the AGXT gene).Types of hyperoxaluria also include: type 2 primary (GRHPR-associated),type 3 primary (DHDPSL-associated), and idiopathic forms ofhyperoxaluria.

The buildup of oxalate in the body causes increased excretion ofoxalate, which in turn results in renal and bladder stones. Stones causeurinary obstruction (often with severe and acute pain), secondaryinfection of urine and eventually kidney damage.

Oxalate stones in primary hyperoxaluria tend to be severe, resulting inrelatively early kidney damage (e.g., onset in teenage years to earlyadulthood), which impairs the excretion of oxalate, leading to a furtheracceleration in accumulation of oxalate in the body.

After the development of renal failure, patients may get deposits ofoxalate in the bones, joints and bone marrow. Severe cases may develophaematological problems such as anaemia and thrombocytopaenia. Thedeposition of oxalate in the body is sometimes called “oxalosis” to bedistinguished from “oxaluria” which refers to oxalate in the urine.

Renal failure is a serious complication requiring treatment in its ownright. Dialysis can control renal failure but tends to be inadequate todispose of excess oxalate. Renal transplant is more effective and thisis the primary treatment of severe hyperoxaluria. Liver transplantation(often in addition to renal transplant) may be able to control thedisease by correcting the metabolic defect.

In a proportion of patients with primary hyperoxaluria type 1,pyridoxine treatment (vitamin B6) may also decrease oxalate excretionand prevent kidney stone formation. Lactate dehydrogenase is known toact as a dismutase converting glyoxylate to oxalate and glycolate (seeFIG. 2). Without wishing to be bound by theory, because an accumulationof oxalate has been identified to cause PH1, inhibition of the enzymesthat produce oxalate represents a therapeutic strategy for treatment ofPH1. As the final enzyme acting within the oxalate synthesis pathway inthe liver, LDH presents an attractive target—especially forliver-targeted dsRNAs, such as LNP-delivered DsiRNAs—for treatment orprevention of PH1.

Primary Types 2 and 3 (PH2 and PH3), and Idiopathic Hyperoxaluria LHD isan attractive drug therapy target for metabolic disorders that result inoxalate accumulation. While not wishing to be bound by theory, PH1 andPH2 have bene described as hereditary disorders of glyoxylate metabolismcaused by deficiency of alanine:glyoxylate-aminotransferase (AGT)(Danpure and Jennings, FEBS Lett 1986; 201: 20-24) and glyoxylatereductase/hydroxypyruvate reductase (GRHPR) (Nephrol. Dial. Transplant.(1995) 10 (supp8): 58-60), respectively. When the activity of theseenzymes is absent or reduced, LDH can convert glyoxylate into excessamounts of oxalate, which accumulates without degradation.

PH3, caused by mutations in HOGA1 (formerly DHDPSL), was recentlyidentified (Belostotsky et al Am J Hum Genet 2010; 87:392-399). Patientswith PH3 often experience calcium oxalate stone disease early in life,with 50% of them presenting with kidney stones before age 5. Data fromthe Rare Kidney Stone Consortium Primary Hyperoxaluria Registry hassuggested that PH3 accounts for approximately 10% of patients with PH ofknown type. All forms of the PH disease share the common feature ofover-production of oxalate from glyoxylate, a reaction catalyzed by LDH.LDH inhibitors such as the dsNAs described herein can thus providerelief to patients of all known forms of PH, as well as to patientshaving idiopathic forms of hyperoxaluria.

Oncology

LHDA is also an attractive target for cancer therapy because it isrequired for the initiation, maintenance and progression of tumors (Shiand Pinto, PLOS ONE January 2014, Volume 9, Issue 1, e86365; Le et al.Proc Natl Acad Sci USA 107: 2037-2042). Up-regulation of LDHA is acharacteristic of many cancer types (Goldman R D et al., Cancer Res 24:389-399.; Koukourakis M I, et al., Br J Cancer 89: 877-885.; KoukourakisM I, et al., LJ Clin Oncol 24: 4301-4308.; Kolev Y, et al., Ann SurgOncol 15: 2336-2344.; Zhuang L, et al., Mod Pathol 23: 45-53),including, e.g., breast cancer, lymphoma, renal cancer (including renalcell cancer tumors), hereditary leiomyomatosis, pancreatic cancer, livercancer (including hepatocellular carcinoma), and other forms of cancer.

Cancer cells preferentially undergo glycolysis followed by fermentation,even under aerobic conditions (Warburg O. London: Arnold Constable;1930; Hanahan and Weinberg Cell 144: 646-674; Ward and Thompson, CBCancer Cell 21: 297-308; Warburg O, Science 124: 269-270) and depend onLDHA for the conversion of pyruvate to lactate. It was shown thathereditary leiomyomatosis and renal cancer tumors overexpressed LDHA andthat LDHA inhibition resulted in increased apoptosis in these cells (XieH, et al., Mol Cancer Ther 2009; 8(3)). Inhibition of LDHA also impairedcell survival in carcinoma cells (Billiard et al., Cancer & Metabolism2013, 1:19). LHDA inhibitors were also shown to induce lymphomaregression (Le et al. Proc Nati Acad Sci USA 107: 2037-2042).

LDHA is an attractive target for cancer therapy also because it ismainly expressed in skeletal muscle and is not present in red bloodcells, in which glycolysis is an obligatory process. Individuals withLDHA deficiency only show myoglobinuria under intense exercise (Kanno T,et al., Clin Chim Acta 1988; 173:89-98; Kanno T, et al., Clin Chim Acta1980; 108:267-76). Also individuals with complete lack of LDHA or LDHBsubunits show no apparent increase in hemolysis (Kanno T, et al., CurrTop Biol Med Res 1983; 7:131-50; Miwa S, et al., Rinsho Byori 1971; 19Suppl:371). It is likely, therefore, that LDHA inhibitors even whendelivered systemically will show only modest toxicity, with moretargeted forms of delivery expected to mitigate any observed toxicityeven further.

Pyruvate Dehydrogenase Deficiency

LHDA is an attractive drug therapy target for metabolic disorders thatresult in lactic acid accumulation. Pyruvate dehydrogenase (PDH)deficiency (also referred to herein as pyruvate dehydrogenase complexdeficiency) is characterized by the buildup of lactic acid in the bodyand by a variety of neurological problems. The metabolic form presentsas severe lactic acidosis with blood lactate concentrations oftenexceeding 10 mmol/l. Treatment is generally aimed at reversing orminimizing systemic lactic acid accumulation (Brown et al., J Med Genet.31 (11): 875-879). LDHA catalyzes the conversion of pyruvate to lactate;therefore, reducing its activity—optionally in conjunction with othertherapy or specialized diet—is likely to provide relief to PDH patients.

Chronic Kidney Disease

In certain aspects of the invention, it was surprisingly identified thattargeting of LDHA with the agents of the invention (e.g., RNAi agents)could provide a therapeutic effect for subjects having chronic kidneydisease. Without wishing to be bound by theory, it is likely thatknockdown of LDHA in a liver-specific manner, which RNAi allows, canprovide a therapeutic impact that is relatively free of deleteriouseffects of loss of LDH activity. In particular, still without wishing tobe bound by theory, it is believed that residual LDH activity providedby, e.g., LDHB, allows for LDHA knockdown in the liver not to produce adeleterious effect, which would otherwise be expected if all LDHactivity in even the liver was eliminated. Meanwhile, other tissues towhich RNAi is currently unable to provide access are believed to benefitfrom not being subject to RNAi-mediated knockdown of LDHA.

Chronic kidney disease (CKD), also known as chronic renal disease, is aprogressive loss in renal function over a period of months or years. Thesymptoms of worsening kidney function are not specific, and can includefeeling generally unwell and experiencing a reduced appetite. Often,chronic kidney disease is diagnosed as a result of screening of peopleknown to be at risk of kidney problems, such as those with high bloodpressure or diabetes and those with a blood relative with CKD. Thisdisease may also be identified when it leads to one of its recognizedcomplications, such as cardiovascular disease, anemia, or pericarditis.It is differentiated from acute kidney disease in that the reduction inkidney function must be present for over 3 months.

Chronic kidney disease is identified by a blood test for creatinine,which is a breakdown product of muscle metabolism. Higher levels ofcreatinine indicate a lower glomerular filtration rate and as a result adecreased capability of the kidneys to excrete waste products.Creatinine levels may be normal in the early stages of CKD, and thecondition is discovered if urinalysis (testing of a urine sample) showsthe kidney is allowing the loss of protein or red blood cells into theurine. To fully investigate the underlying cause of kidney damage,various forms of medical imaging, blood tests, and sometimes a renalbiopsy (removing a small sample of kidney tissue) are employed to findout if a reversible cause for the kidney malfunction is present.

Recent professional guidelines classify the severity of CKD in fivestages, with stage 1 being the mildest and usually causing few symptomsand stage 5 being a severe illness with poor life expectancy ifuntreated. Stage 5 CKD is often called end stage kidney disease, endstage renal disease, or end-stage kidney failure, and is largelysynonymous with the now outdated terms chronic renal failure or chronickidney failure; and usually means the patient requires renal replacementtherapy, which may involve a form of dialysis, but ideally constitutes akidney transplant.

No specific treatment has been unequivocally shown to slow the worseningof CKD. If an underlying cause of CKD, such as vasculitis, orobstructive nephropathy (blockage to the drainage system of the kidneys)is found, it may be treated directly to slow the damage. In moreadvanced stages, treatments may be required for anemia and renal bonedisease (also called renal osteodystrophy, secondary hyperparathyroidismor chronic kidney disease—mineral bone disorder (CKD-MBD)). Chronickidney disease resulted in 956,000 deaths in 2013, up from 409,000deaths in 1990.

CKD is initially without specific symptoms and is generally onlydetected as an increase in serum creatinine or protein in the urine. Asthe kidney function decreases:

-   -   Blood pressure is increased due to fluid overload and production        of vasoactive hormones created by the kidney via the        renin-angiotensin system, increasing one's risk of developing        hypertension and/or suffering from congestive heart failure.    -   Urea accumulates, leading to azotemia and ultimately uremia        (symptoms ranging from lethargy to pericarditis and        encephalopathy). Due to its high systemic circulation, urea is        excreted in eccrine sweat at high concentrations and        crystallizes on skin as the sweat evaporates (“uremic frost”).    -   Potassium accumulates in the blood (hyperkalemia with a range of        symptoms including malaise and potentially fatal cardiac        arrhythmias). Hyperkalemia usually does not develop until the        glomerular filtration rate falls to less than 20-25 ml/min/1.73        m2, at which point the kidneys have decreased ability to excrete        potassium. Hyperkalemia in CKD can be exacerbated by acidemia        (which leads to extracellular shift of potassium) and from lack        of insulin.    -   Erythropoietin synthesis is decreased causing anemia.    -   Fluid volume overload symptoms may range from mild edema to        life-threatening pulmonary edema.    -   Hyperphosphatemia, due to reduced phosphate excretion, follows        the decrease in glomerular filtration. Hyperphosphatemia is        associated with increased cardiovascular risk, being a direct        stimulus to vascular calcification.    -   Hypocalcemia, due to 1,25 dihydroxyvitamin D3 deficiency, is        caused by stimulation of fibroblast growth factor-23. Osteocytes        are responsible for the increased production of FGF23, which is        a potent inhibitor of the enzyme 1-alpha-hydroxylase        (responsible for the conversion of 25-hydroxycholecalciferol        into 1,25 dihydroxyvitamin D3). Later, this progresses to        secondary hyperparathyroidism, renal osteodystrophy, and        vascular calcification that further impairs cardiac function.    -   Metabolic acidosis (due to accumulation of sulfates, phosphates,        uric acid etc.) may cause altered enzyme activity by excess acid        acting on enzymes; and also increased excitability of cardiac        and neuronal membranes by the promotion of hyperkalemia due to        excess acid (acidemia). Acidosis is also due to decreased        capacity to generate enough ammonia from the cells of the        proximal tubule.    -   Iron deficiency anemia, which increases in prevalence as kidney        function decreases, is especially prevalent in those requiring        haemodialysis. It is multifactoral in cause, but includes        increased inflammation, reduction in erythropoietin, and        hyperuricemia leading to bone marrow suppression.

People with CKD suffer from accelerated atherosclerosis and are morelikely to develop cardiovascular disease than the general population.Patients afflicted with CKD and cardiovascular disease tend to havesignificantly worse prognoses than those suffering only from the latter.

Sexual dysfunction is very common in both men and women with CKD. Amajority of men have a reduced sex drive, difficulty obtaining anerection, and reaching orgasm, and the problems get worse with age. Amajority of women have trouble with sexual arousal, and painfulmenstruation and problems with performing and enjoying sex are common.

Diagnosis of CKD is largely based on the clinical picture combined withthe measurement of the serum creatinine level (see above). In many CKDpatients, previous renal disease or other underlying diseases arealready known. A significant number present with CKD of unknown cause.In these patients, a cause is occasionally identified retrospectively.

It is important to differentiate CKD from acute kidney injury (AKI)because AKI can be reversible. Abdominal ultrasound, in which the sizeof the kidneys is measured, is commonly performed. Kidneys with CKD areusually smaller (≤9 cm) than normal kidneys, with notable exceptionssuch as in early diabetic nephropathy and polycystic kidney disease.Another diagnostic clue that helps differentiate CKD from AKI is agradual rise in serum creatinine (over several months or years) asopposed to a sudden increase in the serum creatinine (several days toweeks). If these levels are unavailable (because the patient has beenwell and has had no blood tests), it is occasionally necessary to treata patient briefly as having AKI until the renal impairment has beenestablished to be irreversible.

Additional tests may include nuclear medicine MAG3 scan to confirm bloodflow and establish the differential function between the two kidneys.Dimercaptosuccinic acid (DMSA) scans are also used in renal imaging;with both MAG3 and DMSA being used chelated with the radioactive elementtechnetium-99.

In CKD numerous uremic toxins accumulate in the blood. Even when ESKD(largely synonymous with CKD5) is treated with dialysis, the toxinlevels do not go back to normal as dialysis is not that efficient.Similarly, after a renal transplant, the levels may not go back tonormal as the transplanted kidney may not work 100%. If it does, thecreatinine level is often normal. The toxins show various cytotoxicactivities in the serum and have different molecular weights, and someof them are bound to other proteins, primarily to albumin. Such toxicprotein-bound substances are receiving the attention of scientists whoare interested in improving the standard chronic dialysis proceduresused today.

Screening those who have neither symptoms nor risk factors for CKD isnot recommended. Those who should be screened include: those withhypertension or history of cardiovascular disease, those with diabetesor marked obesity, those aged >60 years, subjects with indigenous racialorigin, those with a history of renal disease in the past, and subjectswho have relatives who had kidney disease requiring dialysis. Screeningshould include calculation of estimated GFR from the serum creatininelevel, and measurement of urine-to-albumin creatinine ratio (ACR) in afirst-morning urine specimen (this reflects the amount of a proteincalled albumin in the urine), as well as a urine dipstick screen forhematuria. The GFR (glomerular filtration rate) is derived from theserum creatinine and is proportional to 1/creatinine, ie it is areciprocal relationship (the higher the creatinine, the lower the GFR).It reflects one aspect of kidney function: how efficiently the glomeruli(filtering units) work. But as they make up <5% of the mass of thekidney, the GFR does not tell you about all aspects of kidney health andfunction. This can be done by combining the GFR level with the clinicalassessment of the patient (especially fluid state) and measuring thelevels of hemoglobin, potassium, phosphate and parathyroid hormone(PTH). Normal GFR is 90-120 mls/min. The units of creatinine vary fromcountry to country.

Guidelines for referral to a nephrologist vary between countries. Thoughmost would agree that nephrology referral is required by Stage 4 CKD(when eGFR/1.73m2 is less than 30 ml/min; or decreasing by more than 3ml/min/year); and may be useful at an earlier stage (eg CKD3) when urinealbumin-to-creatinine ratio is more than 30 mg/mmol, when blood pressureis difficult to control, or when hematuria or other findings suggesteither a primarily glomerular disorder or secondary disease amenable tospecific treatment. Other benefits of early nephrology referral includeproper patient education regarding options for renal replacement therapyas well as pre-emptive transplantation, and timely workup and placementof an arteriovenous fistula in those patients opting for futurehemodialysis

All individuals with a glomerular filtration rate (GFR)<60 ml/min/1.73m² for 3 months are classified as having chronic kidney disease,irrespective of the presence or absence of kidney damage. The rationalefor including these individuals is that reduction in kidney function tothis level or lower represents loss of half or more of the adult levelof normal kidney function, which may be associated with a number ofcomplications such as the development of cardiovascular disease.

The loss of protein in the urine is regarded as an independent markerfor worsening of renal function and cardiovascular disease. Hence,British guidelines append the letter “P” to the stage of chronic kidneydisease if protein loss is significant.

Stage 1

Slightly diminished function; kidney damage with normal or relativelyhigh GFR (≥90 ml/min/1.73 m²). Kidney damage is defined as pathologicalabnormalities or markers of damage, including abnormalities in blood orurine tests or imaging studies.

Stage 2

Mild reduction in GFR (60-89 ml/min/1.73 m2) with kidney damage. Kidneydamage is defined as pathological abnormalities or markers of damage,including abnormalities in blood or urine tests or imaging studies.

Stage 3

Moderate reduction in GFR (30-59 ml/min/1.73 m2): British guidelinesdistinguish between stage 3A (GFR 45-59) and stage 3B (GFR 30-44) forpurposes of screening and referral.

Stage 4

Severe reduction in GFR (15-29 ml/min/1.73 m2) Preparation for renalreplacement therapy.

Stage 5

Established kidney failure (GFR <15 ml/min/1.73 m2), permanent renalreplacement therapy, or end-stage kidney disease.

The term nondialysis dependent CKD (NDD-CKD) is a designation used toencompass the status of those persons with an established CKD who do notyet require the life-supporting treatments for renal failure known asrenal replacement therapy (RRT, including maintenance dialysis or renaltransplantation). The condition of individuals with CKD, who requireeither of the two types of renal replacement therapy (dialysis ortransplant), is referred to as the end-stage renal disease (ESRD).Hence, the start of the ESRD is practically the irreversible conclusionof the NDD-CKD. Even though the NDD-CKD status refers to the status ofpersons with earlier stages of CKD (stages 1 to 4), patients withadvanced stage of CKD (stage 5), who have not yet started renalreplacement therapy, are also referred to as NDD-CKD.

The presence of CKD confers a markedly increased risk of cardiovasculardisease, and people with CKD often have other risk factors for heartdisease, such as high blood lipids. The most common cause of death inpeople with CKD is cardiovascular disease rather than renal failure.Aggressive treatment of hyperlipidemia is warranted.

Apart from controlling other risk factors, the goal of therapy is toslow down or halt the progression of CKD to stage 5. Control of bloodpressure and treatment of the original disease, whenever feasible, arethe broad principles of management. Generally, angiotensin convertingenzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs)are used, as they have been found to slow the progression of CKD informs of the disease with increased levels of protein in the urine.Although the use of ACE inhibitors and ARBs represents the currentstandard of care for people with CKD, people progressively lose kidneyfunction while on these medications, as seen in the IDNT and RENALstudies, which reported a decrease over time in estimated GFR (anaccurate measure of CKD progression, as detailed in the K/DOQIguidelines) in people treated by these conventional methods.

Replacement of erythropoietin and calcitriol, two hormones processed bythe kidney, is often necessary in people with advanced disease.Guidelines recommend treatment with parenteral iron prior to treatmentwith erythropoietin. A target hemoglobin level of 9-12 g/dl isrecommended. The normalization of hemoglobin has not been found to be ofbenefit. It is unclear if androgens help with anemia. Phosphate bindersare also used to control the serum phosphate levels, which are usuallyelevated in advanced chronic kidney disease. Although the evidence forthem is limited, phosphodiesterase-5 inhibitors and zinc show potentialfor helping men with sexual dysfunction.

At stage 5 CKD, renal replacement therapy is usually required, in theform of either dialysis or a transplant.

The prognosis of patients with chronic kidney disease is guarded asepidemiological data have shown that all cause mortality (the overalldeath rate) increases as kidney function decreases. The leading cause ofdeath in patients with chronic kidney disease is cardiovascular disease,regardless of whether there is progression to stage 5.

While renal replacement therapies can maintain patients indefinitely andprolong life, the quality of life is severely affected. Renaltransplantation increases the survival of patients with stage 5 CKDsignificantly when compared to other therapeutic options; however, it isassociated with an increased short-term mortality due to complicationsof the surgery. Transplantation aside, high-intensity home hemodialysisappears to be associated with improved survival and a greater quality oflife, when compared to the conventional three-times-a-week hemodialysisand peritoneal dialysis.

Patients with ESKD are at increased overall risk for cancer. This riskis particularly high in younger patients and gradually diminishes withage. Medical specialty professional organizations recommend thatphysicians do not perform routine cancer screening in patients withlimited life expectancies due to ESKD because evidence does not showthat such tests lead to improved patient outcomes.

Chronic kidney disease resulted in 956,000 deaths in 2013 up from409,000 deaths in 1990.

In Canada, 1.9 to 2.3 million people have CKD.[23] In the US, theCenters for Disease Control and Prevention found that CKD affected anestimated 16.8% of adults aged 20 years and older, during 1999 to 2004.UK estimates suggest that 8.8% of the population of Great Britain andNorthern Ireland have symptomatic CKD.

CKD is a major concern in African Americans, mostly due to increasedprevalence of hypertension. As an example, 37% of ESKD cases in AfricanAmericans can be attributed to high blood pressure, compared with 19%among Caucasians. Treatment efficacy also differs between racial groups.Administration of antihypertensive drugs generally halts diseaseprogression in white populations, but has little effect in slowing renaldisease among blacks, and additional treatment such as bicarbonatetherapy is often required. While lower socioeconomic status contributesto prevalence of CKD, significant differences in CKD prevalence arestill evident between African Americans and Whites when controlling forenvironmental factors. Studies have shown a true association betweenhistory of chronic kidney disease in first- or second-degree relatives,and risk of disease. In addition, African Americans may have higherserum levels of human leukocyte antigens (HLA). High HLA concentrationscan contribute to increased systemic inflammation, which indirectly maylead to heightened susceptibility for developing kidney disease. Lack ofnocturnal reduction in blood pressure among groups of African Americansis also offered as an explanation, which lends further credence to agenetic etiology of CKD racial disparities.

A high and so-far unexplained incidence of CKD, referred to as theMesoamerican nephropathy, has been noted among male workers in CentralAmerica, mainly in sugar cane fields in the lowlands of El Salvador andNicaragua. Heat stress from long hours of piece-rate work at highaverage temperatures (in the range of 96° F.) is suspected, as areagricultural chemicals and other factors. In Sri Lanka, another epidemicof CKD of unknown etiology has become a serious public health concern.

Currently, several compounds are in development for CKD. These includebardoxolone methyl, olmesartan medoxomil, sulodexide, and avosentan. Itis contemplated that the agents set forth herein could be used alone orin combination with such therapies, e.g., to treat chronic kidneydisease.

While the above-recited diseases and/or disorders are specificallyidentified herein as targets for LDHA knockdown, it is also contemplatedthat LDHA knockdown that is either systemic or that is selective for atissue other than, e.g., liver and/or neoplasia tissue (even including,e.g., muscle tissue), could also exert therapeutic benefit within thecorrect patient population(s). Accordingly, delivery of the agents ofthe invention in a manner that is systemic or that preferentiallytargets tissues other than those most accessible to LNPs (such as liver,pancreatic, kidney, neoplasia and/or blood tissues) is alsocontemplated. Thus, the LDHA knockdown agents of the invention canoptionally be targeted to lung, brain, lymphatic, muscle, etc. tissues.

Exemplary dsNA Structures

Certain aspects of the invention employ dsNA structures to knock downthe LDHA target in cells and/or in a subject. Exemplary dsNA structuresinclude the following:

In certain embodiments of the invention, tetraloop- and modifiednucleotide-containing dsNAs are contemplated as described, e.g., in US2011/0288147. In certain such embodiments, a dsNA of the inventionpossesses a first strand and a second strand, where the first strand andthe second strand form a duplex region of 19-25 nucleotides in length,wherein the first strand comprises a 3′ region that extends beyond thefirst strand-second strand duplex region and comprises a series oflinking nucleotides, optionally a tetraloop, and the dsNA comprises adiscontinuity between the 3′ terminus of the first strand and the 5′terminus of the second strand. Optionally, the discontinuity ispositioned at a projected dicer cleavage site of thetetraloop-containing dsNA.

In some embodiments, the DsiRNA of the instant invention furthercomprises a linking moiety or domain that joins the sense and antisensestrands of a dsNA of the invention, e.g., a DNA:DNA-extended DsiRNAagent. Optionally, such a linking moiety domain joins the 3′ end of thesense strand and the 5′ end of the antisense strand. The linking moietymay be a chemical (non-nucleotide) linker, such as an oligomethylenediollinker, oligoethylene glycol linker, or other art-recognized linkermoiety. Alternatively, the linker can be a nucleotide linker, optionallyincluding an extended loop and/or tetraloop.

In one embodiment of the present invention, each oligonucleotide of aDsiRNA molecule of the invention is independently 19 to 80 nucleotidesin length, in specific embodiments 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80 ormore nucleotides in length. For dsNAs possessing a strand that exceeds30 nucleotides in length, available structures include those where onlyone strand exceeds 30 nucleotides in length (see, e.g., U.S. Pat. No.8,349,809, where an exemplary double stranded nucleic acid possesses afirst oligonucleotide strand having a 5′ terminus and a 3′ terminus anda second oligonucleotide strand having a 5′ terminus and a 3′ terminus,where each of the 5′ termini has a 5′ terminal nucleotide and each ofthe 3′ termini has a 3′ terminal nucleotide, where the first strand is15-30 nucleotide residues in length, where starting from the 5′ terminalnucleotide (position 1) positions 1 to 15 of the first strand include atleast 8 ribonucleotides; the second strand is 36-80 nucleotide residuesin length and, starting from the 3′ terminal nucleotide, includes atleast 8 ribonucleotides in the positions paired with positions 1-15 ofthe first strand to form a duplex; where at least the 3′ terminalnucleotide of the second strand is unpaired with the first strand, andup to 6 consecutive 3′ terminal nucleotides are unpaired with the firststrand, thereby forming a 3′ single stranded overhang of 1-6nucleotides; where the 5′ terminus of the second strand includes from5-64 consecutive nucleotides which are unpaired with the first strand,thereby forming a 5-64 nucleotide single stranded 5′ overhang; where atleast the first strand 5′ terminal and 3′ terminal nucleotides are basepaired with nucleotides of the second strand when the first and secondstrands are aligned for maximum complementarity, thereby forming asubstantially duplexed region between the first and second strands; andthe second strand is sufficiently complementary to a target RNA along atleast 19 ribonucleotides of the second strand length to reduce targetgene expression when the double stranded nucleic acid is introduced intoa mammalian cell).

In another exemplary embodiment of dsNA structures of the invention, thefirst strand possesses a 5′-overhang region of 5-61 nucleotides inlength, adjacent to the duplex region of sufficient complementaritybetween first and second strands to allow for duplex formation, wherethe 3′-terminus of the first strand and the 5′-terminus of the secondstrand form a blunt structure or form a second strand 5′-overhang of thefirst strand (e.g., of 1-6 nucleotides in length), where the secondstrand includes a sequence of at least 19 nucleotides sufficientlycomplementary to the target LDHA transcript to effect knockdown of LDHAwhen introduced to mammalian cells.

RNAi therapies are newly identified to provide an attractive, targetedmeans of treating PH1, PH2, PH3, idiopathic hyperoxaluria, pyruvatedehydrogenase deficiency, chronic kidney disease, cancer and otherconditions, diseases or disorders for which reduction of LDH levels,particularly in the liver, can prove therapeutic or otherwiseadvantageous, at a molecular level. Notably, RNAi therapies, such as thedsRNAs that are specifically exemplified herein, have demonstratedparticularly good ability to be delivered to the cells of the liver invivo (via, e.g., lipid nanoparticles and/or conjugates such as dynamicpolyconjugates or GalNAc conjugates—in certain exemplary embodiments,GalNAc can be conjugated to a 3′- and/or 5′-overhang region of a dsNA,optionally to an “extended” overhang region of a dsNA (e.g., to a 5 ormore nucleotide, 8 or more nucleotide, etc. example of such anoverhang); additionally and/or alternatively, GalNAc can be conjugatedto ds extended regions of a dsNA, e.g., to the duplex region formed bythe 5′-end region of the guide/antisense strand of a dsNA and thecorresponding 3′-end region of the passenger/sense strand of a dsNAand/or to the duplex region formed by the 3′-end region of theguide/antisense strand of a dsNA and the corresponding 5′-end region ofthe passenger/sense strand of a dsNA). Thus, formulated RNAi therapies,such as those described herein, are attractive modalities for treatingor preventing diseases or disorders that are present in, originate in orotherwise involve the liver (e.g., PH1, oxalate accumulation and/orother lactate dehydrogenase-associated diseases or disorders).

Even though a number of embodiments of the invention are directed toliver-targeted delivery of anti-lactate dehydrogenase dsRNAs, use ofRNAi therapies to target lactate dehydrogenase at a molecular level inother tissues is also contemplated.

The dsRNA agents of the invention when formulated in delivery vehiclesknown in the art, e.g., lipid nanoparticles (LNPs) are known to targetliver cells more readily than cells of other organs. This effect can beused to therapeutic advantage by avoiding induction of lactatedehydrogenase deficiency in non-liver cells during liver-specifictargeting of LDH. Lactate dehydrogenase deficiency is a condition thataffects how the body breaks down sugar to use as energy in cells,primarily muscle cells. There are two types of this condition: lactatedehydrogenase-A deficiency (sometimes called glycogen storage diseaseXI) and lactate dehydrogenase-B deficiency. People with lactatedehydrogenase-A deficiency experience fatigue, muscle pain, and crampsduring exercise (exercise intolerance). In some people with lactatedehydrogenase-A deficiency, high-intensity exercise or other strenuousactivity leads to the breakdown of muscle tissue (rhabdomyolysis). Thedestruction of muscle tissue releases a protein called myoglobin, whichis processed by the kidneys and released in the urine (myoglobinuria).Myoglobin causes the urine to be red or brown. This protein can alsodamage the kidneys, in some cases leading to life-threatening kidneyfailure. Some people with lactate dehydrogenase-A deficiency developskin rashes. The severity of the signs and symptoms among individualswith lactate dehydrogenase-A deficiency varies greatly. People withlactate dehydrogenase-B deficiency typically do not have any signs orsymptoms of the condition. They do not have difficulty with physicalactivity or any specific physical features related to the condition.Affected individuals are usually discovered only when routine bloodtests reveal reduced lactate dehydrogenase activity.

Lactate Dehydrogenase cDNA and Polypeptide Sequences

Known human and mouse lactate dehydrogenase (lactate dehydrogenase A orLDHA) cDNA and polypeptide sequences include the following: humanlactate dehydrogenase NM_005566.3 and corresponding human lactatedehydrogenase polypeptide sequence GenBank Accession No. NP_005557.1;and mouse wild-type lactate dehydrogenase sequence GenBank Accession No.NM_001136069.2 (Mus musculus C57BL/6 Ldha, transcript variant 2) andcorresponding mouse Ldha polypeptide sequence GenBank Accession No.NP_001129541.2. Other forms of mammalian lactate dehydrogenase includeLDHB (NM_002300.6 and NM_008492.2; NP_002291.1 and NP_032518.1) and LDHC(NM_002301.4 and NM_013580.4; NP_002292.1 and NP_030698.1). It iscontemplated that certain of the LDHA-targeting nucleic acids of theinvention can also be used to target one or more of these additionalforms of LDH, in certain instances for therapeutic benefit. Additionallyand/or alternatively, combination therapies are contemplated thatinclude both an LDHA-targeting nucleic acid of the invention and one ormore inhibitors of LDHB and/or LDHC, in certain instances for addedtherapeutic benefit.

Assessment of Lactate Dehydrogenase Levels

In certain embodiments, dsRNA-mediated inhibition of a lactatedehydrogenase target sequence is assessed. In such embodiments, lactatedehydrogenase RNA levels can be assessed by art-recognized methods(e.g., RT-PCR, Northern blot, expression array, etc.), optionally viacomparison of lactate dehydrogenase levels in the presence of ananti-lactate dehydrogenase dsRNA of the invention relative to theabsence of such an anti-lactate dehydrogenase dsRNA. In certainembodiments, lactate dehydrogenase levels in the presence of ananti-lactate dehydrogenase dsRNA are compared to those observed in thepresence of vehicle alone, in the presence of a dsRNA directed againstan unrelated target RNA, or in the absence of any treatment.

It is also recognized that levels of lactate dehydrogenase protein canbe assessed and that lactate dehydrogenase protein levels are, underdifferent conditions, either directly or indirectly related to lactatedehydrogenase RNA levels and/or the extent to which a dsRNA inhibitslactate dehydrogenase expression, thus art-recognized methods ofassessing lactate dehydrogenase protein levels (e.g., Western blot,immunoprecipitation, other antibody-based methods, etc.) can also beemployed to examine the inhibitory effect of a dsRNA of the invention.

In certain embodiments, potency of a dsRNA of the invention isdetermined in reference to the number of copies of a dsRNA present inthe cytoplasm of a target cell that are required to achieve a certainlevel of target gene knockdown. For example, in certain embodiments, apotent dsRNA is one capable of causing 50% or greater knockdown of atarget mRNA when present in the cytoplasm of a target cell at a copynumber of 1000 or fewer RISC-loaded antisense strands per cell. Morepreferably, a potent dsRNA is one capable of producing 50% or greaterknockdown of a target mRNA when present in the cytoplasm of a targetcell at a copy number of 500 or fewer RISC-loaded antisense strands percell. Optionally, a potent dsRNA is one capable of producing 50% orgreater knockdown of a target mRNA when present in the cytoplasm of atarget cell at a copy number of 300 or fewer RISC-loaded antisensestrands per cell.

In further embodiments, the potency of a DsiRNA of the invention can bedefined in reference to a 19 to 23mer dsRNA directed to the same targetsequence within the same target gene. For example, a DsiRNA of theinvention that possesses enhanced potency relative to a corresponding 19to 23mer dsRNA can be a DsiRNA that reduces a target gene by anadditional 5% or more, an additional 10% or more, an additional 20% ormore, an additional 30% or more, an additional 40% or more, or anadditional 50% or more as compared to a corresponding 19 to 23mer dsRNA,when assayed in an in vitro assay as described herein at a sufficientlylow concentration to allow for detection of a potency difference (e.g.,transfection concentrations at or below 1 nM in the environment of acell, at or below 100 pM in the environment of a cell, at or below 10 pMin the environment of a cell, at or below 1 nM in the environment of acell, in an in vitro assay as described herein; notably, it isrecognized that potency differences can be best detected via performanceof such assays across a range of concentrations—e.g., 0.1 pM to 10nM—for purpose of generating a dose-response curve and identifying anIC₅₀ value associated with a DsiRNA/dsRNA).

In certain embodiments, a nucleic acid of the invention is administeredin an amount sufficient to reduce lactate dehydrogenase target mRNAexpression when the nucleic acid is introduced into a mammalian cell. Inexemplary embodiments, reduction of lactate dehydrogenase target mRNAexpression is assessed to have occurred if lactate dehydrogenase targetmRNA levels are decreased by at least 5% or more, 10% or more, 20% ormore, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more,80% or more, or 90% or more, as compared to a corresponding mammaliancell administered an appropriate control that does not include thelactate dehydrogenase-targeting nucleic acid of the invention. In anexemplary embodiment, the mammalian cell used to determine whetherreduction of lactate dehydrogenase target mRNA expression has occurredrelative to an appropriate control is a HeLa cell, and the lactatedehydrogenase-targeting nucleic acid of the invention is optionallyadministered via transfection (e.g., using Lipofectamine™) at aconcentration of at or below 1 nM in the environment of a cell, at orbelow 100 pM in the environment of a cell, at or below 10 pM in theenvironment of a cell, at or below 1 nM in the environment of a cell, inan in vitro assay as described herein.

Lactate dehydrogenase inhibitory levels and/or lactate dehydrogenaselevels may also be assessed indirectly, e.g., measurement of a reducedlevel of PH1 and/or associated phenotypes, and/or other phenotypesassociated with oxalate accumulation, can indicate lactate dehydrogenaseinhibitory efficacy of a double-stranded nucleic acid of the instantinvention.

Models Useful to Evaluate the Down-Regulation of Lactate DehydrogenasemRNA Levels and Expression

Therapeutic agents can be tested in selected animal model(s). Forexample, a dsRNA agent (or expression vector or transgene encoding same)as described herein can be used in an animal model to determine theefficacy, toxicity, or side effects of treatment with said agent.Alternatively, an agent (e.g., a therapeutic agent) can be used in ananimal model to determine the mechanism of action of such an agent.

Cell Culture

The dsRNA agents of the invention can be tested for cleavage activity invivo, for example, using the following procedure. The nucleotidesequences within the lactate dehydrogenase cDNA targeted by the dsRNAagents of the invention are shown in the above lactate dehydrogenasesequences.

The dsRNA reagents of the invention can be tested in cell culture usingHeLa or other mammalian cells (e.g., human cell lines Hep3B, HepG2,DU145, Calu3, SW480, T84, PL45, Huh7 etc., and mouse cell lines B16-F10,AML12, Neuro2a, etc.) to determine the extent of lactate dehydrogenaseRNA and lactate dehydrogenase protein inhibition. In certainembodiments, DsiRNA reagents (e.g., see FIG. 1, and exemplary structuresrecited elsewhere herein) are selected against the lactate dehydrogenasetarget as described herein, lactate dehydrogenase RNA inhibition ismeasured after delivery of these reagents by a suitable transfectionagent to, for example, cultured HeLa cells or other transformed ornon-transformed mammalian cells in culture. Relative amounts of targetlactate dehydrogenase RNA are measured versus HPRT1, actin or otherappropriate control using real-time PCR monitoring of amplification(e.g., ABI 7700 TAQMAN®). A comparison is made to the activity ofoligonucleotide sequences made to unrelated targets or to a randomizedDsiRNA control with the same overall length and chemistry, or simply toappropriate vehicle-treated or untreated controls. Primary and secondarylead reagents are chosen for the target and optimization performed.

TAQMAN® (Real-Time PCR Monitoring of Amplification) and LightcyclerQuantification of mRNA

Total RNA is prepared from cells following DsiRNA delivery, for example,using Ambion Rnaqueous 4-PCR purification kit for large scaleextractions, or Promega SV96 for 96-well assays. For Taqman analysis,dual-labeled probes are synthesized with, for example, the reporter dyesFAM or VIC covalently linked at the 5′-end and the quencher dye TAMRAconjugated to the 3′-end. PCR amplifications are performed on, forexample, an ABI PRISM 7700 Sequence detector using 50 uL reactionsconsisting of 10 uL total RNA, 100 nM forward primer, 100 mM reverseprimer, 100 nM probe, 1×TaqMan PCR reaction buffer (PE-AppliedBiosystems), 5.5 mM MgCl2, 100 uM each dATP, dCTP, dGTP and dTTP, 0.2 URNase Inhibitor (Promega), 0.025 U AmpliTaq Gold (PE-Applied Biosystems)and 0.2 U M-MLV Reverse Transcriptase (Promega). The thermal cyclingconditions can consist of 30 minutes at 48° C., 10 minutes at 95° C.,followed by 40 cycles of 15 seconds at 95° C. and 1 minute at 60° C.Quantitation of target lactate dehydrogenase mRNA level is determinedrelative to standards generated from serially diluted total cellular RNA(300, 100, 30, 10 ng/r×n) and normalizing to, for example, HPRT1 mRNA ineither parallel or same tube TaqMan reactions.

Western Blotting

Cellular protein extracts can be prepared using a standard micropreparation technique (for example using RIPA buffer), or preferably, byextracting nuclear proteins by a method such as the NE-PER Nuclear andCytoplasmic Extraction kit (Thermo-Fisher Scientific). Cellular proteinextracts are run on Tris-Glycine polyacrylamide gel and transferred ontomembranes. Non-specific binding can be blocked by incubation, forexample, with 5% non-fat milk for 1 hour followed by primary antibodyfor 16 hours at 4° C. Following washes, the secondary antibody isapplied, for example (1:10,000 dilution) for 1 hour at room temperatureand the signal detected on a VersaDoc imaging system

In several cell culture systems, cationic lipids have been shown toenhance the bioavailability of oligonucleotides to cells in culture(Bennet, et al., 1992, Mol. Pharmacology, 41, 1023-1033). In oneembodiment, dsRNA molecules of the invention are complexed with cationiclipids for cell culture experiments. dsRNA and cationic lipid mixturesare prepared in serum-free OptimMEM (InVitrogen) immediately prior toaddition to the cells. OptiMEM is warmed to room temperature (about20-25° C.) and cationic lipid is added to the final desiredconcentration. dsRNA molecules are added to OptiMEM to the desiredconcentration and the solution is added to the diluted dsRNA andincubated for 15 minutes at room temperature. In dose responseexperiments, the RNA complex is serially diluted into OptiMEM prior toaddition of the cationic lipid.

Animal Models

The efficacy of anti-lactate dehydrogenase dsRNA agents may be evaluatedin an animal model. Animal models of PH1, and/or diseases, conditions,or disorders associated with oxalate accumulation or LDHA overexpressionas are known in the art can be used for evaluation of the efficacy,potency, toxicity, etc. of anti-lactate dehydrogenase dsRNAs. Exemplaryanimal models of PH1 include, e.g., Agxt1 knockout mice. Animal modelsmay be used as a source of cells or tissue for assays of thecompositions of the invention. Such models can also be used or adaptedfor use for pre-clinical evaluation of the efficacy of dsRNAcompositions of the invention in modulating lactate dehydrogenase geneexpression toward therapeutic use.

Such models and/or wild-type mice can be used in evaluating the efficacyof dsRNA molecules of the invention to inhibit lactate dehydrogenaselevels, expression, development of lactate dehydrogenase-associatedphenotypes, diseases or disorders, etc. These models, wild-type miceand/or other models can similarly be used to evaluate thesafety/toxicity and efficacy of dsRNA molecules of the invention in apre-clinical setting.

Specific examples of animal model systems useful for evaluation of thelactate dehydrogenase-targeting dsRNAs of the invention includewild-type mice and Agxt1 knockout mice (see, e.g., Hernandez-Fernaud andSalido (FEBS Journal 277: 4766-74)). In an exemplary in vivo experiment,dsRNAs of the invention are tail vein injected into such mouse models atdoses ranging from 1 to 10 mg/kg or, alternatively, repeated doses areadministered at single-dose IC₅₀ levels, and organ samples (e.g., liver,but may also include prostate, kidney, lung, pancreas, colon, skin,spleen, bone marrow, lymph nodes, mammary fat pad, etc.) are harvested24 hours after administration of the final dose. Such organs are thenevaluated for mouse and/or human lactate dehydrogenase levels, dependingupon the model used. Duration of action can also be examined at, e.g.,1, 4, 7, 14, 21 or more days after final dsRNA administration.

Lactate Dehydrogenase-Targeting dsRNAs

In certain embodiments, an anti-lactate dehydrogenase DsiRNA of theinstant invention possesses strand lengths of at least 25 nucleotides.Accordingly, in certain embodiments, an anti-lactate dehydrogenaseDsiRNA contains one oligonucleotide sequence, a first sequence, that isat least 25 nucleotides in length and no longer than 35 or up to 50 ormore nucleotides. This sequence of RNA can be between 26 and 35, 26 and34, 26 and 33, 26 and 32, 26 and 31, 26 and 30, and 26 and 29nucleotides in length. This sequence can be 27 or 28 nucleotides inlength or 27 nucleotides in length. The second sequence of the DsiRNAagent can be a sequence that anneals to the first sequence underbiological conditions, such as within the cytoplasm of a eukaryoticcell. Generally, the second oligonucleotide sequence will have at least19 complementary base pairs with the first oligonucleotide sequence,more typically the second oligonucleotide sequence will have 21 or morecomplementary base pairs, or 25 or more complementary base pairs withthe first oligonucleotide sequence. In one embodiment, the secondsequence is the same length as the first sequence, and the DsiRNA agentis blunt ended. In another embodiment, the ends of the DsiRNA agent haveone or more overhangs.

In certain embodiments, the first and second oligonucleotide sequencesof the DsiRNA agent exist on separate oligonucleotide strands that canbe and typically are chemically synthesized. In some embodiments, bothstrands are between 26 and 35 nucleotides in length. In otherembodiments, both strands are between 25 and 30 or 26 and 30 nucleotidesin length. In one embodiment, both strands are 27 nucleotides in length,are completely complementary and have blunt ends. In certain embodimentsof the instant invention, the first and second sequences of ananti-lactate dehydrogenase DsiRNA exist on separate RNA oligonucleotides(strands). In one embodiment, one or both oligonucleotide strands arecapable of serving as a substrate for Dicer. In other embodiments, atleast one modification is present that promotes Dicer to bind to thedouble-stranded RNA structure in an orientation that maximizes thedouble-stranded RNA structure's effectiveness in inhibiting geneexpression. In certain embodiments of the instant invention, theanti-lactate dehydrogenase DsiRNA agent is comprised of twooligonucleotide strands of differing lengths, with the anti-lactatedehydrogenase DsiRNA possessing a blunt end at the 3′ terminus of afirst strand (sense strand) and a 3′ overhang at the 3′ terminus of asecond strand (antisense strand). The DsiRNA can also contain one ormore deoxyribonucleic acid (DNA) base substitutions.

Suitable DsiRNA compositions that contain two separate oligonucleotidescan be chemically linked outside their annealing region by chemicallinking groups. Many suitable chemical linking groups are known in theart and can be used. Suitable groups will not block Dicer activity onthe DsiRNA and will not interfere with the directed destruction of theRNA transcribed from the target gene. Alternatively, the two separateoligonucleotides can be linked by a third oligonucleotide such that ahairpin structure is produced upon annealing of the two oligonucleotidesmaking up the DsiRNA composition. The hairpin structure will not blockDicer activity on the DsiRNA and will not interfere with the directeddestruction of the target RNA.

The dsRNA molecule can be designed such that every residue of theantisense strand is complementary to a residue in the target molecule.Alternatively, substitutions can be made within the molecule to increasestability and/or enhance processing activity of said molecule.Substitutions can be made within the strand or can be made to residuesat the ends of the strand. In certain embodiments, substitutions and/ormodifications are made at specific residues within a DsiRNA agent. Suchsubstitutions and/or modifications can include, e.g.,deoxy—modifications at one or more residues of positions 1, 2 and 3 whennumbering from the 3′ terminal position of the sense strand of a DsiRNAagent; and introduction of 2′-O-alkyl (e.g., 2′-O-methyl) modificationsat the 3′ terminal residue of the antisense strand of DsiRNA agents,with such modifications also being performed at overhang positions ofthe 3′ portion of the antisense strand and at alternating residues ofthe antisense strand of the DsiRNA that are included within the regionof a DsiRNA agent that is processed to form an active siRNA agent. Thepreceding modifications are offered as exemplary, and are not intendedto be limiting in any manner. Further consideration of the structure ofpreferred DsiRNA agents, including further description of themodifications and substitutions that can be performed upon theanti-lactate dehydrogenase DsiRNA agents of the instant invention, canbe found below.

A dsRNA of the invention comprises two RNA strands that are sufficientlycomplementary to hybridize to form a duplex structure. One strand of thedsRNA (the antisense strand) comprises a region of complementarity thatis substantially complementary, and generally fully complementary, to atarget sequence, derived from the sequence of an mRNA formed during theexpression of the lactate dehydrogenase target gene, the other strand(the sense strand) comprises a region which is complementary to theantisense strand, such that the two strands hybridize and form a duplexstructure when combined under suitable conditions. Generally, the duplexstructure is between 15 and 35, optionally between 25 and 30, between 26and 30, between 18 and 25, between 19 and 24, or between 19 and 21 basepairs in length. Similarly, the region of complementarity to the targetsequence is between 15 and 35, optionally between 18 and 30, between 25and 30, between 19 and 24, or between 19 and 21 nucleotides in length.The dsRNA of the invention may further comprise one or moresingle-stranded nucleotide overhang(s). It has been identified thatdsRNAs comprising duplex structures of between 15 and 35 base pairs inlength can be effective in inducing RNA interference, including DsiRNAs(generally of at least 25 base pairs in length) and siRNAs (in certainembodiments, duplex structures of siRNAs are between 20 and 23, andoptionally, specifically 21 base pairs (Elbashir et al., EMBO 20:6877-6888)). It has also been identified that dsRNAs possessing duplexesshorter than 20 base pairs can be effective as well (e.g., 15, 16, 17,18 or 19 base pair duplexes). In certain embodiments, the dsRNAs of theinvention can comprise at least one strand of a length of 19 nucleotidesor more. In certain embodiments, it can be reasonably expected thatshorter dsRNAs comprising a sequence complementary to one of thesequences of Tables 4, 6, 9 or 11, minus only a few nucleotides on oneor both ends may be similarly effective as compared to the dsRNAsdescribed above and in Tables 2-3, 7-8 and 12. Hence, dsRNAs comprisinga partial sequence of at least 15, 16, 17, 18, 19, 20, or morecontiguous nucleotides sufficiently complementary to one of thesequences of Tables 4, 6, 9 or 11, and differing in their ability toinhibit the expression of the lactate dehydrogenase target gene in anassay as described herein by not more than 5, 10, 15, 20, 25, or 30%inhibition from a dsRNA comprising the full sequence, are contemplatedby the invention. In one embodiment, at least one end of the dsRNA has asingle-stranded nucleotide overhang of 1 to 5, optionally 1 to 4, incertain embodiments, 1 or 2 nucleotides. Certain dsRNA structures havingat least one nucleotide overhang possess superior inhibitory propertiesas compared to counterparts possessing base-paired blunt ends at bothends of the dsRNA molecule.

In one embodiment, dsRNA molecules of the invention that down regulateor reduce lactate dehydrogenase gene expression are used for treating,preventing or reducing lactate dehydrogenase-related diseases ordisorders (e.g., PH1 or other disease or disorder associated withoxalate accumulation, and/or oncology or pyruvate dehydrogenasedeficiency) in a subject or organism.

In some embodiments, both strands exceed 30 nucleotides in length (see,e.g., U.S. Pat. No. 8,513,207, where an exemplary double strandednucleic acid (dsNA) possesses a first oligonucleotide strand having a 5′terminus and a 3′ terminus and a second oligonucleotide strand having a5′ terminus and a 3′ terminus, where the first strand is 31 to 49nucleotide residues in length, where starting from the first nucleotide(position 1) at the 5′ terminus of the first strand, positions 1 to 23of the first strand are ribonucleotides; the second strand is 31 to 53nucleotide residues in length and includes 23 consecutiveribonucleotides that base pair with the ribonucleotides of positions 1to 23 of the first strand to form a duplex; the 5′ terminus of the firststrand and the 3′ terminus of said second strand form a blunt end or a1-4 nucleotide 3′ overhang; the 3′ terminus of the first strand and the5′ terminus of said second strand form a duplexed blunt end, a 5′overhang or a 3′ overhang; optionally, at least one of positions 24 tothe 3′ terminal nucleotide residue of the first strand is adeoxyribonucleotide, optionally, that base pairs with adeoxyribonucleotide of said second strand; and the second strand issufficiently complementary to a target RNA along at least 19ribonucleotides of the second strand length to reduce target geneexpression when the double stranded nucleic acid is introduced into amammalian cell).

In certain embodiments, an active dsNA of the invention can possess a 5′overhang of the first strand (optionally, the passenger strand) withrespect to the second strand (optionally, the guide strand) of 2-50nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) or morein length. In related embodiments, the duplex region formed by the firstand second strands of such a dsNA is 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or more base pairs in length. The 5′ overhang “extended” regionof the first strand is optionally modified at one or more residues(optionally, at alternating residues, all residues, or any otherselection of residues).

In certain embodiments, an active dsNA of the invention can possess a 3′overhang of the first strand (optionally, the passenger strand) withrespect to the second strand (optionally, the guide strand) of 2-50nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) or morein length. In related embodiments, the duplex region formed by the firstand second strands of such a dsNA is 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or more base pairs in length. The 3′ overhang “extended” regionof the first strand is optionally modified at one or more residues(optionally, at alternating residues, all residues, or any otherselection of residues).

In another embodiment of the present invention, each sequence of aDsiRNA molecule of the invention is independently 25 to 35 nucleotidesin length, in specific embodiments 25, 26, 27, 28, 29, 30, 31, 32, 33,34 or 35 nucleotides in length. In another embodiment, the DsiRNAduplexes of the invention independently comprise 25 to 30 base pairs(e.g., 25, 26, 27, 28, 29, or 30). In another embodiment, one or morestrands of the DsiRNA molecule of the invention independently comprises19 to 35 nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34 or 35) that are complementary to a target (lactatedehydrogenase) nucleic acid molecule. In certain embodiments, a DsiRNAmolecule of the invention possesses a length of duplexed nucleotidesbetween 25 and 34 nucleotides in length (e.g., 25, 26, 27, 28, 29, 30,31, 32, 33 or 34 nucleotides in length; optionally, all such nucleotidesbase pair with cognate nucleotides of the opposite strand). (ExemplaryDsiRNA molecules of the invention are shown in FIG. 1, and below.)

Stabilizing modifications (e.g., 2′-O-Methyl, phosphorothioate,deoxyribonucleotides, including dNTP base pairs, 2′-F, etc.) can beincorporated within any double stranded nucleic acid of the invention,and can be used in abundance, particularly within DsiRNAs possessing oneor both strands exceeding 30 nucleotides in length.

In certain embodiments, at least 10%, at least 20%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95% or more of the nucleotide residuesof a nucleic acid of the instant invention are modified residues. For adsNA of the invention, at least 10%, at least 20%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95% or more of the nucleotide residuesof the first strand are modified residues. Additionally and/oralternatively for a dsNA of the invention, at least 10%, at least 20%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95% or more of thenucleotide residues of the second strand are modified residues. For thedsNAs of the invention, modifications of both duplex (double-stranded)regions and overhang (single-stranded) regions are contemplated. Thus,in certain embodiments, at least 10%, at least 20%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95% or more (e.g., all) duplexnucleotide residues are modified residues. Additionally and/oralternatively, at least 10%, at least 20%, at least 30%, at least 35%,at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or more (e.g., all) overhang nucleotide residuesof one or both strands are modified residues. Optionally, themodifications of the dsNAs of the invention do not include an invertedabasic (e.g., inverted deoxy abasic) or inverted dT end-protectinggroup. Alternatively, a dsNA of the invention includes a terminal capmoiety (e.g., an inverted deoxy abasic and/or inverted dT end-protectinggroup). Optionally, such a terminal cap moiety is located at the 5′ end,at the 3′ end, or at both the 5′ end and the 3′ end of the first strand,of the second strand, or of both first and second strands.

While the guide strand of a double stranded nucleic acid of theinvention must possess a sequence of, e.g., 15, 16, 17, 18 or 19nucleotides that are complementary to a target RNA (e.g., mRNA),additional sequence(s) of the guide strand need not be complementary tothe target RNA. The end structures of double stranded nucleic acidspossessing at least one strand length in excess of 30 nucleotides canalso be varied while continuing to yield functional dsNAs—e.g. the 5′end of the guide strand and the 3′ end of the passenger strand may forma 5′-overhang, a blunt end or a 3′ overhang (for certain dsNAs, e.g.,“single strand extended” dsNAs, the length of such a 5′ or 3′ overhangcan be 1-4, 1-5, 1-6, 1-10, 1-15, 1-20 or even 1-25 or more); similarly,the 3′ end of the guide strand and the 5′ end of the passenger strandmay form a 5′-overhang, a blunt end or a 3′ overhang (for certain dsNAs,e.g., “single strand extended” dsNAs, the length of such a 5′ or 3′overhang can be 1-4, 1-5, 1-6, 1-10, 1-15, 1-20 or even 1-25 or more).In certain embodiments, the length of the passenger strand is 31-49nucleotides while the length of the guide strand is 31-53 nucleotides,optionally while the 5′ end of the guide strand forms a blunt end(optionally, a base-paired blunt end) with the 3′ end of the passengerstrand, optionally, with the 3′ end of the guide strand and the 5′ endof the passenger strand forming a 3′ overhang of 1-4 nucleotides inlength. Exemplary “extended” Dicer substrate structures are set forth,e.g., in US 2010/0173974 and U.S. Pat. No. 8,349,809, both of which areincorporated herein by reference. In certain embodiments, one or morestrands of the dsNA molecule of the invention independently comprises 19to 35 nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34 or 35) that are complementary to a target (lactatedehydrogenase) nucleic acid molecule. In certain embodiments, a DsiRNAmolecule of the invention possesses a length of duplexed nucleotidesbetween 25 and 66 nucleotides, optionally between 25 and 49 nucleotidesin length (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80 nucleotides in length; optionally, all suchnucleotides base pair with cognate nucleotides of the opposite strand).In related embodiments, a dsNA of the invention possesses strand lengthsthat are, independently, between 19 and 80 nucleotides in length,optionally between 25 and 53 nucleotides in length, e.g., 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80 nucleotides in length. In certain embodiments,one strand length is 19-35 nucleotides in length, while the other strandlength is 30-80 nucleotides in length and at least one strand has a 5′overhang of at least 5 nucleotides in length relative to the otherstrand. In certain related embodiments, the 3′ end of the first strandand the 5′ end of the second strand form a structure that is a blunt endor a 1-6 nucleotide 3′ overhang, while the 5′ end of the first strandforms a 5-60 nucleotide overhang with respect to the 3′ end of thesecond strand. Optionally, between one and all nucleotides of the 5-60nucleotide overhang are modified nucleotides (optionally,deoxyribonucleotides and/or modified ribonucleotides).

In some embodiments, a dsNA of the invention has a first or secondstrand that has at least 8 contiguous ribonucleotides. In certainembodiments, a dsNA of the invention has 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23 or more (e.g., 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 26, or more, up to the full length of the strand)ribonucleotides, optionally including modified ribonucleotides(2′-O-methyl ribonucleotides, phosphorothioate linkages, etc.). Incertain embodiments, the ribonucleotides or modified ribonucleotides arecontiguous.

In certain embodiments, a dsNA comprising a first strand and a secondstrand, each strand, independently, having a 5′ terminus and a 3′terminus, and having, independently, respective strand lengths of 25-53nucleotides in length, is sufficiently highly modified (e.g., at least10% or more, at least 20% or more, at least 30% or more, at least 40% ormore, at least 50% or more, at least 60% or more, at least 70% or more,at least 80% or more, at least 90% or more, at least 95% or moreresidues of one and/or both strands are modified such that dicercleavage of the dsNA is prevented (optionally, modified residues occurat and/or flanking one or all predicted dicer cleavage sites of thedsNA). Such non-dicer-cleaved dsNAs retain LDH inhibition activity andare optionally cleaved by non-dicer nucleases to yield, e.g., 15-30, orin particular embodiments, 19-23 nucleotide strand length dsNAs capableof inhibiting LDH in a mammalian cell. In certain related embodiments,dsNAs possessing sufficiently extensive modification to block dicercleavage of such dsNAs optionally possess regions of unmodifiednucleotide residues (e.g., one or two or more consecutive nucleotides,forming a “gap” or “window” in a modification pattern) that allow forand/or promote cleavage of such dsNAs by non-Dicer nucleases. In otherembodiments, Dicer-cleaved dsNAs of the invention can include extensivemodification patterns that possess such “windows” or “gaps” inmodification such that Dicer cleavage preferentially occurs at suchsites (as compared to heavily modified regions within such dsNAs).

In certain embodiments, a DsiRNA (in a state as initially formed, priorto dicer cleavage) is more potent at reducing lactate dehydrogenasetarget gene expression in a mammalian cell than a 19, 20, 21, 22 or 23base pair sequence that is contained within it. In certain suchembodiments, a DsiRNA prior to dicer cleavage is more potent than a19-21mer contained within it. Optionally, a DsiRNA prior to dicercleavage is more potent than a 19 base pair duplex contained within itthat is synthesized with symmetric dTdT overhangs (thereby forming asiRNA possessing 21 nucleotide strand lengths having dTdT overhangs). Incertain embodiments, the DsiRNA is more potent than a 19-23mer siRNA(e.g., a 19 base pair duplex with dTdT overhangs) that targets at least19 nucleotides of the 21 nucleotide target sequence that is recited fora DsiRNA of the invention (without wishing to be bound by theory, theidentity of a such a target site for a DsiRNA is identified viaidentification of the Ago2 cleavage site for the DsiRNA; once the Ago2cleavage site of a DsiRNA is determined for a DsiRNA, identification ofthe Ago2 cleavage site for any other inhibitory dsRNA can be performedand these Ago2 cleavage sites can be aligned, thereby determining thealignment of projected target nucleotide sequences for multiple dsRNAs).In certain related embodiments, the DsiRNA is more potent than a19-23mer siRNA that targets at least 20 nucleotides of the 21 nucleotidetarget sequence that is recited for a DsiRNA of the invention.Optionally, the DsiRNA is more potent than a 19-23mer siRNA that targetsthe same 21 nucleotide target sequence that is recited for a DsiRNA ofthe invention. In certain embodiments, the DsiRNA is more potent thanany 21 mer siRNA that targets the same 21 nucleotide target sequencethat is recited for a DsiRNA of the invention. Optionally, the DsiRNA ismore potent than any 21 or 22mer siRNA that targets the same 21nucleotide target sequence that is recited for a DsiRNA of theinvention. In certain embodiments, the DsiRNA is more potent than any21, 22 or 23mer siRNA that targets the same 21 nucleotide targetsequence that is recited for a DsiRNA of the invention. As noted above,such potency assessments are most effectively performed upon dsRNAs thatare suitably formulated (e.g., formulated with an appropriatetransfection reagent) at a concentration of 1 nM or less. Optionally, anIC₅₀ assessment is performed to evaluate activity across a range ofeffective inhibitory concentrations, thereby allowing for robustcomparison of the relative potencies of dsRNAs so assayed.

The dsRNA molecules of the invention are added directly, or can becomplexed with lipids (e.g., cationic lipids), packaged withinliposomes, or otherwise delivered to target cells or tissues. Thenucleic acid or nucleic acid complexes can be locally administered torelevant tissues ex vivo, or in vivo through direct dermal application,transdermal application, or injection, with or without theirincorporation in biopolymers. In particular embodiments, the nucleicacid molecules of the invention comprise sequences shown in FIG. 1, andthe below exemplary structures. Examples of such nucleic acid moleculesconsist essentially of sequences defined in these figures and exemplarystructures. Furthermore, where such agents are modified in accordancewith the below description of modification patterning of DsiRNA agents,chemically modified forms of constructs described in FIG. 1, and thebelow exemplary structures can be used in all uses described for theDsiRNA agents of FIG. 1, and the below exemplary structures.

In another aspect, the invention provides mammalian cells containing oneor more dsRNA molecules of this invention. The one or more dsRNAmolecules can independently be targeted to the same or different sites.

Modified Structures of Anti-Lactate Dehydrogenase DsiRNA Agents

In certain embodiments, the anti-lactate dehydrogenase DsiRNA agents ofthe invention can have the following structures:

In one such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers. In a relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand.

DsiRNAs of the invention can carry a broad range of modificationpatterns (e.g., 2′-O-methyl RNA patterns, e.g., within extended DsiRNAagents). Certain modification patterns of the second strand of DsiRNAsof the invention are presented below.

In one embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers, and“D”=DNA. The top strand is the sense strand, and the bottom strand isthe antisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7” or “M7”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. The top strand is the sense strand, and the bottomstrand is the antisense strand. In another related embodiment, theDsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6” or “M6”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5” or “M5”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4” or “M4”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8” or “M8”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M3” or “M3”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2” or “M2”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M1” or “M1”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M9” or “M9”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10” or “M10”modification pattern.

In further embodiments the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11” or “M11”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M12” or “M12”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13” or “M13”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M21” or “M21”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14” or “M14”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15” or “M15”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16” or “M16”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17” or “M17”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18” or “M18”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19” or “M19”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20” or “M20”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” s an overhang domain comprisedof 1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers,underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22” or “M22”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24” or “M24”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25” or “M25”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26” or “M26”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27” or “M27”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28” or “M28”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29” or “M29”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M30” or “M30”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M31” or “M31”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M32” or “M32”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34” or “M34”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35” or “M35”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37” or “M37”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38” or “M38”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40” or “M40”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41” or “M41”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M36” or “M36”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M42” or “M42”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M43” or “M43”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M44” or “M44”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M45” or “M45”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M46” or “M46”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M47” or “M47”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M48” or “M48”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M52” or “M52”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M54” or “M54”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M55” or “M55”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M56” or “M56”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M57” or “M57”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M58” or “M58”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M59” or “M59”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M60” or “M60”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M61” or “M61”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M62” or “M62”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M63” or “M63”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M64” or “M64”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M65” or “M65”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M66” or “M66”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M67” or “M67”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M68” or “M68”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M69” or “M69”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M70” or “M70”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M71” or “M71”modification pattern. In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M72” or “M72”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M73” or “M73”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7*” or “M7*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6*” or “M6*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5*” or “M5*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4*” or “M4*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8*” or “M8*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2*” or “M2*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10*” or“M10*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11*” or“M11*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13*” or“M13*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14*” or“M14*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15*” or“M15*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16*” or“M16*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17*” or“M17*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18*” or“M18*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19*” or“M19*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20*” or“M20*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22*” or“M22*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24*” or“M24*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25*” or“M25*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26*” or“M26*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27*” or“M27*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28*” or“M28*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29*” or“M29*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34*” or“M34*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35*” or“M35*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37*” or“M37*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38*” or“M38*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40*” or“M40*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41*” or“M41*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M36*” or“M36*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M42*” or“M42*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M43*” or“M43*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M44*” or“M44*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M46*” or“M46*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M47*” or“M47*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M48*” or“M48*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M52*” or“M52*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M54*” or“M54*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M55*” or“M55*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M56*” or“M56*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M57*” or“M57*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M58*” or“M58*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M59*” or“M59*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M60*” or“M60*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M61*” or“M61*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M62*” or“M62*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M63*” or“M63*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M64*” or“M64*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M65*” or“M65*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M66*” or“M66*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M67*” or“M67*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M68*” or“M68*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M69*” or“M69*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M70*” or“M70*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M71*” or“M71*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M72*” or“M72*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M73*” or“M73*” modification pattern.

Additional exemplary antisense strand modifications include thefollowing:

3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M74”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M75”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M76”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M77”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M78”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M79”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M80”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M81”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M82”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M83”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M84”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M85”3′-FFFXXXXXXXXXXXXXXXXXXXXFFFF-5′ “AS-M88”3′-XXXXFXXXFXFXXXXXXXXXXXXXXXX-5′ “AS-M89”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M90”3′-FFFXXXXXXXXXXXXXXXXXXXXXXFF-5′ “AS-M91”3′-XXXXXXFXXXXXFXFXXXXXXXXXXXX-5′ “AS-M92”3′-FFFXFXXXXXXXXXXXXXFXXXXXXXX-5′ “AS-M93”3′-FFFXFXFXXXXXFXFXFXFXXXXFFFF-5′ “AS-M94”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M95”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′ “AS-M96”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M210”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M74*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M75*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M76*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M77*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M78*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M79*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M80*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M82*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M83*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M84*”3′-XFFXXXXXXXXXXXXXXXXXXXXFFFF-5′ “AS-M88*”3′-XXXXFXXXFXFXXXXXXXXXXXXXXXX-5′ “AS-M89*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M90*”3′-XFFXXXXXXXXXXXXXXXXXXXXXXFF-5′ “AS-M91*”3′-XXXXXXFXXXXXFXFXXXXXXXXXXXX-5′ “AS-M92*”3′-XFFXFXXXXXXXXXXXXXFXXXXXXXX-5′ “AS-M93*”3′-XFFXFXFXXXXXFXFXFXFXXXXFFFF-5′ “AS-M94*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M95*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′ “AS-M96*”3′-XxXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M210*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M101”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M104”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M104*”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M105”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M105*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M106”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M106*”3′-XXpXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M107”3′-XXpXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M107*”3′-ba-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M108” (ba = inverted abasic forF7 stabi- lization at 3′ end) 3′-ba-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′“AS-M108*” (ba = inverted abasic for F7 stabi- lization at 3′ end)3′-XDXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M109”3′-XpXXFXFXFXXXXXXXXXXXXXXXXXXpX-5′ “AS-M110”3′-XpXXFXFXFXXXXXXXXXXXXXXXXXXpX-5′ “AS-M110*”3′-XpXXFXFXFXXXXXFXFXFXFXXXXXXpX-5′ “AS-M111”3′-XpXXFXFXFFXXXXXXXXXXFXXXXXXpX-5′ “AS-M112”3′-XpXXFXFXFFXXFXXXXXXXFXXXXXXpX-5′ “AS-M113”3′-XpXXFXFXFFFFFXXXXXXXFXXXXXXpX-5′ “AS-M114”3′-XpXXFXFXFFFFFXXXXXXXFXXFXXXpX-5′ “AS-M115”3′-XpXXFXFXFFFFFXXXXXXXFFFFXXXpX-5′ “AS-M116”3′-XpFXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M117”3′-XpXXFXFXFXXXXXFXFXFXFXXXXXXpX-5′ “AS-M111*”3′-XpXXFXFXFFXXXXXXXXXXFXXXXXXpX-5′ “AS-M112*”3′-XpXXFXFXFFXXFXXXXXXXFXXXXXXpX-5′ “AS-M113*”3′-XpXXFXFXFFFFFXXXXXXXFXXXXXXpX-5′ “AS-M114*”3′-XpXXFXFXFFFFFXXXXXXXFXXFXXXpX-5′ “AS-M115*”3′-XpXXFXFXFFFFFXXXXXXXFFFFXXXpX-5′ “AS-M116*”3′-XpFXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M117*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M120”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M121”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M122”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M123”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M124”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M125”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M126”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M127”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M128”3′-XpFpXFXFXFXFXFXFXFXFXFXFFFFFpF-5′ “AS-M129”3′-XpFpXFXFXFXFXFXFXFXFXFXXXFXFpX-5′ “AS-M130”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M131”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M132”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M133”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFFFpF-5′ “AS-M134”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M135”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M136”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M137”3′-XXXFXFXFXXXXXFXFXFXFXXXXXXX-5′ “AS-M138”3′-XXXFXFXFFXXXXXXXXXXFXXXXXXX-5′ “AS-M139”3′-XpXXFXFXFXXXXXFXFXFFFXXXXXXpX-5′ “AS-M140”3′-XpXXFXFXFFXXXFFXFXFFFXXXXXXpX-5′ “AS-M141”3′-XpXXFXFXFXFXFXFXFXFFFXXXXXXpX-5′ “AS-M142”3′-XpXXFXFXFFFFFFFXFXFFFXXXXXXpX-5′ “AS-M143”3′-XpXXFXFXFXFXFXFXFXFpXpFpXXXXXXpX- “AS-M144” 5′3′-XXXXXXXXXXXXXXXXFXXXXXXXXXX-5′ “AS-M145”3′-XXXXXXXXXXXXXXFXXXXXXXXXXXX-5′ “AS-M146”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M147”3′-XXXXXXXXXXFXXXXXXXXXXXXXXXX-5′ “AS-M148”3′-XXXXXXXXXXXXFXXXXXXXXXXXXXX-5′ “AS-M149”3′-XXXXXXXXXXFXFXXXXXXXXXXXXXX-5′ “AS-M150”3′-XXXXXXXXXXXXFXXXFXXXXXXXXXX-5′ “AS-M151”3′-XXXXXXXXXXFXXXFXXXXXXXXXXXX-5′ “AS-M152”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M153”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M154”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M155”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M156”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M157”3′-XpXXFXFFFFXXXFXXFXXFFXXXXXXpX-5′ “AS-M158”3′-XpXXFXFFFFFFFFXXFXXFFXXXXXXpX-5′ “AS-M159”3′-XpXXFXXXFXXXXXFXFXXFFXXXXXXpX-5′ “AS-M160”3′-XpXXFXXXFXFXFXFXFXXFFXXXXXXpX-5′ “AS-M161”3′-XXXXXXXXFXFXFXXXXXXXXXXXXXX-5′ “AS-M162”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M163”3′-XXXXXXXXDXXXXXXXXXXXXXXXXXX-5′ “AS-M164”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M120*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M121*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M122*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M123*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M124*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M125*”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M126*”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M127*”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M128*”3′-XpFpXFXFXFXFXFXFXFXFXFXFFFFFpF-5′ “AS-M129*”3′-XpFpXFXFXFXFXFXFXFXFXFXXXFXFpX-5′ “AS-M130*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M131*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M132*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M133*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFFFpF-5′ “AS-M134*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M135*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M136*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M137*”3′-XXXFXFXFXXXXXFXFXFXFXXXXXXX-5′ “AS-M138*”3′-XXXFXFXFFXXXXXXXXXXFXXXXXXX-5′ “AS-M139*”3′-XpXXFXFXFXXXXXFXFXFFFXXXXXXpX-5′ “AS-M140*”3′-XpXXFXFXFFXXXFFXFXFFFXXXXXXpX-5′ “AS-M141*”3′-XpXXFXFXFXFXFXFXFXFFFXXXXXXpX-5′ “AS-M142*”3′-XpXXFXFXFFFFFFFXFXFFFXXXXXXpX-5′ “AS-M143*”3′-XpXXFXFXFXFXFXFXFXFpXpFpXXXXXXpX- “AS-M144*” 5′3′-XXXXXXXXXXXXXXXXFXXXXXXXXXX-5′ “AS-M145*”3′-XXXXXXXXXXXXXXFXXXXXXXXXXXX-5′ “AS-M146*”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M147*”3′-XXXXXXXXXXFXXXXXXXXXXXXXXXX-5′ “AS-M148*”3′-XXXXXXXXXXXXFXXXXXXXXXXXXXX-5′ “AS-M149*”3′-XXXXXXXXXXFXFXXXXXXXXXXXXXX-5′ “AS-M150*”3′-XXXXXXXXXXXXFXXXFXXXXXXXXXX-5′ “AS-M151*”3′-XXXXXXXXXXFXXXFXXXXXXXXXXXX-5′ “AS-M152*”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M153*”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M154*”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M155*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M156*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M157*”3′-XpXXFXFFFFXXXFXXFXXFFXXXXXXpX-5′ “AS-M158*”3′-XpXXFXFFFFFFFFXXFXXFFXXXXXXpX-5′ “AS-M159*”3′-XpXXFXXXFXXXXXFXFXXFFXXXXXXpX-5′ “AS-M160*”3′-XpXXFXXXFXFXFXFXFXXFFXXXXXXpX-5′ “AS-M161*”3′-XXXXXXXXFXFXFXXXXXXXXXXXXXX-5′ “AS-M162*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M163*”3′-XXXXXXXXDXXXXXXXXXXXXXXXXXX-5′ “AS-M164*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M211”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M212”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M215”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M216”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M217”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M218”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M219”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M220”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M221”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M222”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M223”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M224”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M225”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M226”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M230”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M231”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M232”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M233”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M234”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M235”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M236”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M237”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M238”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M239”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M240”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M241”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M242”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M243”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M244”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M245”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M246”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M247”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M248”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M249”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M250”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M251”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M252”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M253”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M254”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M255”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M211*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M212*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M215*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M216*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M217*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M218*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M219*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M220*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M221*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M222*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M223*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M224*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M225*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M226*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M230*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M231*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M232*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M233*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M234*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M235*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M236*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M237*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M238*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M239*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M240*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M241*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M242*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M243*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M244*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M245*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M246*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M247*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M248*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M249*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M250*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M251*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M252*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M253*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M254*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M255*”where “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and“p”=Phosphorothioate linkage.

In certain additional embodiments, the antisense strand of selecteddsRNAs of the invention are extended, optionally at the 5′ end, with anexemplary 5′ extension of base “AS-M8”, “AS-M17” and “AS-M48”modification patterns respectively represented as follows:

(SEQ ID NO: 3493) 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M8, extended” (SEQ ID NO: 3493)3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M17, extended” (SEQ ID NO: 3493)3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M48, extended”where “X”=RNA; “X”=2′-O-methyl RNA; “F”=2′-Fluoro NA and “A” in bold,italics indicates a 2′-Fluoro-adenine residue.

In certain embodiments, the sense strand of a DsiRNA of the invention ismodified—specific exemplary forms of sense strand modifications areshown below, and it is contemplated that such modified sense strands canbe substituted for the sense strand of any of the DsiRNAs shown above togenerate a DsiRNA comprising a below-depicted sense strand that annealswith an above-depicted antisense strand. Exemplary sense strandmodification patterns include:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM1” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM2” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM3”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM4” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM5” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM6”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM7” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM8” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM9”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM10” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM11” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM12”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM13” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM14” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM15”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM16” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM17” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM18”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM19” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM20” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM21”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM23” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM24” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM25”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM30” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM31” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM32”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM33” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM34” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM35”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM36” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM37” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM38”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM39” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM40” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM41”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM42” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM43” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM44”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM45”, “SM47”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM46” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM48” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM49”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM50” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM51” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM52”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM53” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM54” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM55”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM56” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM57” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM58”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM59” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM60” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM61”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM62” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM63” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM64”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM65” 5′-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′“SM66” 5′-XpXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM67”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM68”5′-DXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM69”5′-DpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM70”5′-DXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM71” 5′-DpXDXXXXXXXXXXXXXXXXXXXXDD-3′“SM72” 5′-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM73”5′-XpXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM74” 5′-DXDXXXXXXXXXDXXXXXDXXXXDD-3′“SM75” 5′-DpXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM76”5′-XpXpXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM77”5′-XpXpXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM78”5′-DpXpDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM79”5′-XpXpDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM80” 5′-DXDXXXDXXXXXDXXXXXDXXXXDD-3′“SM81” 5′-DpXDXXXDXXXXXDXXXXXDXXXXpDpD-3′ “SM82” 5′ C3 spacer- “SM83”XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 5′ C3 spacer- “SM84”XXDXXXXXXXXXDXXXXXXXXXXDD-3′ 5′ C3 spacer- “SM85”XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM86”5′-XpXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM87”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM88”5′-DXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM89”5′-DpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM90”5′-DXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM91” 5′-DpXDXXXXXXXXXXXXXXXXXXXXDD-3′“SM92” 5′-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM93”5′-XpXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM94” 5′-DXDXXXXXXXXXDXXXXXDXXXXDD-3′“SM95” 5′-DpXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM96”5′-XpXpXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM97”5′-XpXpXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM98”5′-DpXpDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM99”5′-XpXpDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM100”5′-DXDXXXXXXXXXDXDXXXDDXXDDD-3′ “SM101”5′-DpXDXXXDXXXXXDXXXXXDXXXXpDpD-3′ “SM102” 5′ C3 spacer- “SM103”XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 5′ C3 spacer- “SM104”XXDXXXXXXXXXDXXXXXXXXXXDD-3′ 5′ C3 spacer- “SM105”XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM106”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM107” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM108” 5′-XFXXXXXXXXXXXXXXXFXXXXXDD-3′ “SM110”5′-XXXFXFXXXXXXXFXXXXXXXXXDD-3′ “SM111” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′“SM112” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′ “SM113”5′-XFXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM114” 5′-XXXXFFXFXXXFXFXXXXXXXXXDD-3′“SM115” 5′-XFXFXXXXXXXXXXXXFXXXXXXDD-3′ “SM116”5′-XFXFFFXFXXXFXFXFFFXXXXXDD-3′ “SM117” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′“SM118” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′ “SM119”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM250” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM251” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM252”5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ “SM22” 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-35′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM120”5′-FpXFXFXFXFXFXFXFXFXFXFXXDpD-3′ “SM121”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM122”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM123”5′-FpXFXXXFXXXXXXXXXXXXXXXXpDpD-3′ “SM124”5′-FpXFXXXFXXXXXFXFXXXXXXXXpDpD-3′ “SM125”5′-FpXFXXXFXFFFXFXFXXXXXXXXpDpD-3′ “SM126”5′-FpXFXXXFXFFFXFXFXXXFFXXXpDpD-3′ “SM127”5′-FpXFXXXFXFFFXFXFXXXFFXXFpDpD-3′ “SM128”5′-FpXFXXXFXFFFXFXFXXXFFFFFpDpD-3′ “SM129”5′-FpXFXFXFXFXFXFXFXFXFXFXFpDpD-3′ “SM130”5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-FpXFXFXFXFXFXFXFXFXFXFXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-FpXFXXXFXXXXXXXXXXXXXXXXpXpX-3′ 5′-FpXFXXXFXXXXXFXFXXXXXXXXpXpX-3′5′-FpXFXXXFXFFFXFXFXXXXXXXXpXpX-3′ 5′-FpXFXXXFXFFFXFXFXXXFFXXXpXpX-3′5′-FpXFXXXFXFFFXFXFXXXFFXXFpXpX-3′ 5′-FpXFXXXFXFFFXFXFXXXFFFFFpXpX-3′5′-FpXFXFXFXFXFXFXFXFXFXFXFpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′“SM133” 5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM134”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM135”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM136”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM137”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM138”5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM140”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM141”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM142”5′-FpXFXFXFXFXFXFXFXFXFXXXFDpD-3′ “SM143”5′-FpXFXFXFXFXFXFXFXFXFFFFFDpD-3′ “SM144”5′-FpXFXFXFXFXFXFXFXFXFXXXXDpD-3′ “SM145”5′-FpXFXFXFXFXFXFXFXFXFXFXFDpD-3′ “SM146”5′-FXFXXXFXFFFXFXFXXXXXXXXDD-3′ “SM147” 5′-FXFXXXFXFFFXFXFXXXFFXXXDD-3′“SM148” 5′-FXFXXXFXFFFXFXFXXXFFXXFDD-3′ “SM149”5′-FXFXXXFXFFFXFXFXXXFFFFFDD-3′ “SM150”5′-FpXFXFXFXFFFXFXFXFXFFXXFDpD-3′ “SM151”5′-FpXFXFXFXFFXFXXFXFXFXXXXDpD-3′ “SM152”5′-FpXFXFXXFFFFFXXFXFXXFXXXDpD-3′ “SM153”5′-ab-XXFXXFFFXXFFXXXFFFFXpXXXDD-3′ “SM154” (ab = abasic for F7stabilization at 5′ end) 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ “SM155”5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ “SM156”5′-FpXFXXXFFFFFFFXXXFXXFXXFXpX-3′ “SM157”5′-XpXFXFXXFFFFXFXFXFXXFXXXXpX-3′ “SM158”5′-FpXFXXXFXFFXFXXFXXXFXXXXXpX-3′ “SM159”5′-FpXFXFXFXFFFXFXFXFXFXXXXXX-3′ “SM160”5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-FpXFXFXFXFXFXFXFXFXFXXXFXpX-3′5′-FpXFXFXFXFXFXFXFXFXFFFFFXpX-3′ 5′-FpXFXFXFXFXFXFXFXFXFXXXXXpX-3′5′-FpXFXFXFXFXFXFXFXFXFXFXFXpX-3′ 5′-FXFXXXFXFFFXFXFXXXXXXXXXX-3′5′-FXFXXXFXFFFXFXFXXXFFXXXXX-3′ 5′-FXFXXXFXFFFXFXFXXXFFXXFXX-3′5′-FXFXXXFXFFFXFXFXXXFFFFFXX-3′ 5′-FpXFXFXFXFFFXFXFXFXFFXXFXpX-3′5′-FpXFXFXFXFFXFXXFXFXFXXXXXpX-3′ 5′-FpXFXFXXFFFFFXXFXFXXFXXXXpX-3′5′-ab-XXFXXFFFXXFFXXXFFFFXpXXXXX-3′ (ab = abasic for F7 stabilization at5′ end) 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-FpXFXXXFFFFFFFXXXFXXFXXFXpX-3′5′-XpXFXFXXFFFFXFXFXFXXFXXXXpX-3′ 5′-FpXFXXXFXFFXFXXFXXXFXXXXXpX-3′5′-FpXFXFXFXFFFXFXFXFXFXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM253”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM255” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM256” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM257”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM258” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM259” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM260”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM261” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM262” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM263”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM264” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM265” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM266”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM267” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM268” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM269”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM270” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM271” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM275”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM276” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM277” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM278”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM279” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM280” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM281”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM282” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM283” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM284”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM285” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM286” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM287”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM288” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM289” 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM300”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM301”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM302”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM303”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM304”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM305”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM306”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM307”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM308”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM309”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM310”5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′where “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and“p”=Phosphorothioate linkage.

The above modification patterns can also be incorporated into, e.g., theextended DsiRNA structures and mismatch and/or frayed DsiRNA structuresdescribed below.

In another embodiment, the DsiRNA comprises strands having equal lengthspossessing 1-3 mismatched residues that serve to orient Dicer cleavage(specifically, one or more of positions 1, 2 or 3 on the first strand ofthe DsiRNA, when numbering from the 3′-terminal residue, are mismatchedwith corresponding residues of the 5′-terminal region on the secondstrand when first and second strands are annealed to one another). Anexemplary 27mer DsiRNA agent with two terminal mismatched residues isshown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed. Any of the residues of such agents can optionallybe 2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In certain additional embodiments, the present invention providescompositions for RNA interference (RNAi) that possess one or more basepaired deoxyribonucleotides within a region of a double strandedribonucleic acid (dsRNA) that is positioned 3′ of a projected sensestrand Dicer cleavage site and correspondingly 5′ of a projectedantisense strand Dicer cleavage site. The compositions of the inventioncomprise a dsRNA which is a precursor molecule, i.e., the dsRNA of thepresent invention is processed in vivo to produce an active smallinterfering nucleic acid (siRNA). The dsRNA is processed by Dicer to anactive siRNA which is incorporated into RISC.

In certain embodiments, the DsiRNA agents of the invention can have thefollowing exemplary structures (noting that any of the followingexemplary structures can be combined, e.g., with the bottom strandmodification patterns of the above-described structures—in one specificexample, the bottom strand modification pattern shown in any of theabove structures is applied to the 27 most 3′ residues of the bottomstrand of any of the following structures; in another specific example,the bottom strand modification pattern shown in any of the abovestructures upon the 23 most 3′ residues of the bottom strand is appliedto the 23 most 3′ residues of the bottom strand of any of the followingstructures):

In one such embodiment, the DsiRNA comprises the following (an exemplary“right-extended”, “DNA extended” DsiRNA):

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)XX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=O to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=O to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X1/D1]_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X2/D2]_(N)ZZ-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, “Z”=DNA or RNA,and “N”=1 to 50 or more, but is optionally 1-8 or 1-10, where at leastone D1_(N) is present in the top strand and is base paired with acorresponding D2_(N) in the bottom strand. Optionally, D1_(N) andD1_(N)+1 are base paired with corresponding D2_(N) and D2_(N)+1; D1_(N),D1_(N)+1 and D1_(N)+2 are base paired with corresponding D2_(N), D1N+1and D1_(N)+2, etc. “N*”=0 to 15 or more, but is optionally 0, 1, 2, 3,4, 5 or 6. In one embodiment, the top strand is the sense strand, andthe bottom strand is the antisense strand. Alternatively, the bottomstrand is the sense strand and the top strand is the antisense strand,with 2′-O-methyl RNA monomers located at alternating residues along thetop strand, rather than the bottom strand presently depicted in theabove schematic.

In the structures depicted herein, the 5′ end of either the sense strandor antisense strand can optionally comprise a phosphate group.

In another embodiment, a DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-15 or, optionally, 1-8. “N*”=0 to 15 or more, but is optionally 0, 1,2, 3, 4, 5 or 6. Any of the residues of such agents can optionally be2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand (first strand) is the sense strand, and the bottom strand (secondstrand) is the antisense strand. Alternatively, the bottom strand is thesense strand and the top strand is the antisense strand. Modificationand DNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In one embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure. Anexemplary structure for such a molecule is shown:

5′-XXXXXXXXXXXXXXXXXXXDDXX-3′ 3′-YXXXXXXXXXXXXXXXXXDDXXXX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. The above structureis modeled to force Dicer to cleave a minimum of a 21 mer duplex as itsprimary post-processing form. In embodiments where the bottom strand ofthe above structure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In one embodiment, the DsiRNA comprises the following (an exemplary“left-extended”, “DNA extended” DsiRNA):

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)XX-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strandis the sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1 to 50 or more, butis optionally 1-8 or 1-10, where at least one D1_(N) is present in thetop strand and is base paired with a corresponding D2_(N) in the bottomstrand. Optionally, DIN and D1_(N)+1 are base paired with correspondingD2_(N) and D2_(N)+1; D1_(N), D1_(N)+1 and D1_(N)+2 are base paired withcorresponding D2_(N), D1_(N)+1 and D1_(N)+2, etc. “N*”=0 to 15 or more,but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the topstrand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In a related embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “D”=DNA, “Y” is an optional overhang domain comprisedof 0-10 RNA monomers that are optionally 2′-O-methyl RNA monomers—incertain embodiments, “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers, and “N”=1 to 50or more, but is optionally 1-8 or 1-10, where at least one DIN ispresent in the top strand and is base paired with a corresponding D2_(N)in the bottom strand. Optionally, D1_(N) and D1_(N+1) are base pairedwith corresponding D2_(N) and D2_(N)+1; D1_(N), D1_(N+1) and D1_(N)+2are base paired with corresponding D2_(N), D1_(N)+1 and D1_(N)+2, etc.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-8 or 1-10. “N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or6. Any of the residues of such agents can optionally be 2′-O-methyl RNAmonomers—alternating positioning of 2′-O-methyl RNA monomers thatcommences from the 3′-terminal residue of the bottom (second) strand, asshown for above asymmetric agents, can also be used in the above“blunt/fray” DsiRNA agent. In one embodiment, the top strand (firststrand) is the sense strand, and the bottom strand (second strand) isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. Modification andDNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In another embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure.Exemplary structures for such a molecule are shown:

5′-XXDDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-DDXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′or 5′-XDXDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-DXDXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. “N*”=0 to 15or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In any of the above embodiments where the bottom strand of the abovestructure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In certain embodiments, the “D” residues of the above structures includeat least one PS-DNA or PS-RNA. Optionally, the “D” residues of the abovestructures include at least one modified nucleotide that inhibits Dicercleavage.

While the above-described “DNA-extended” DsiRNA agents can becategorized as either “left extended” or “right extended”, DsiRNA agentscomprising both left- and right-extended DNA-containing sequences withina single agent (e.g., both flanks surrounding a core dsRNA structure aredsDNA extensions) can also be generated and used in similar manner tothose described herein for “right-extended” and “left-extended” agents.

In some embodiments, the DsiRNA of the instant invention furthercomprises a linking moiety or domain that joins the sense and antisensestrands of a dsNA of the invention, e.g., a DNA:DNA-extended DsiRNAagent. Optionally, such a linking moiety domain joins the 3′ end of thesense strand and the 5′ end of the antisense strand. The linking moietymay be a chemical (non-nucleotide) linker, such as an oligomethylenediollinker, oligoethylene glycol linker, or other art-recognized linkermoiety. Alternatively, the linker can be a nucleotide linker, optionallyincluding an extended loop and/or tetraloop.

In one embodiment, the DsiRNA agent has an asymmetric structure, withthe sense strand having a 25-base pair length, and the antisense strandhaving a 27-base pair length with a 1-4 base 3′-overhang (e.g., a onebase 3′-overhang, a two base 3′-overhang, a three base 3′-overhang or afour base 3′-overhang). In another embodiment, this DsiRNA agent has anasymmetric structure further containing 2 deoxynucleotides at the 3′ endof the sense strand.

In another embodiment, the DsiRNA agent has an asymmetric structure,with the antisense strand having a 25-base pair length, and the sensestrand having a 27-base pair length with a 1-4 base 3′-overhang (e.g., aone base 3′-overhang, a two base 3′-overhang, a three base 3′-overhangor a four base 3′-overhang). In another embodiment, this DsiRNA agenthas an asymmetric structure further containing 2 deoxyribonucleotides atthe 3′ end of the antisense strand.

Exemplary Lactate Dehydrogenase targeting DsiRNA agents of theinvention, and their associated lactate dehydrogenase target sequences,include the following, presented in the below series of tables:

Table Number:

-   (2) Selected Human Anti-Lactate Dehydrogenase DsiRNA Agents    (Asymmetrics);-   (3) Selected Human Anti-Lactate Dehydrogenase DsiRNAs, Unmodified    Duplexes (Asymmetrics);-   (4) DsiRNA Target Sequences (21mers) in Human Lactate Dehydrogenase    mRNA;-   (5) Selected Human Anti-Lactate Dehydrogenase “Blunt/Blunt” DsiRNAs;-   (6) DsiRNA Component 19 Nucleotide Target Sequences in Human Lactate    Dehydrogenase mRNA;-   (7) Selected Mouse Anti-Lactate Dehydrogenase DsiRNA Agents    (Asymmetrics);-   (8) Selected Mouse Anti-Lactate Dehydrogenase DsiRNAs, Unmodified    Duplexes (Asymmetrics);-   (9) DsiRNA Target Sequences (21 mers) in Mouse Lactate Dehydrogenase    mRNA;-   (10) Selected Mouse Anti-Lactate Dehydrogenase “Blunt/Blunt”    DsiRNAs;-   (11) DsiRNA Component 19 Nucleotide Target Sequences in Mouse    Lactate Dehydrogenase mRNA; and-   (12) Additional Selected Human Anti-Lactate Dehydrogenase DsiRNA    Agents (Asymmetrics)

TABLE 2 Selected Human Anti-Lactate Dehydrogenase DsiRNA Agents(Asymmetries) 5′-AGAAUAAGAUUACAGUUGUUGGGgt-3′ (SEQ ID NO: 1)3′-GGUCUUAUUCUAAUGUCAACAACCCCA-5′ (SEQ ID NO: 73) LDHA-355 Target:5′-CCAGAATAAGATTACAGTTGTTGGGGT-3′ (SEQ ID NO: 145)5′-GAAUAAGAUUACAGUUGUUGGGGtt-3′ (SEQ ID NO: 2)3′-GUCUUAUUCUAAUGUCAACAACCCCAA-5′ (SEQ ID NO: 74) LDHA-356 Target:5′-CAGAATAAGATTACAGTTGTTGGGGTT-3′ (SEQ ID NO: 146)5′-AAGAUUACAGUUGUUGGGGUUGGtg-3′ (SEQ ID NO: 3)3′-UAUUCUAAUGUCAACAACCCCAACCAC-5′ (SEQ ID NO: 75) LDHA-360 Target:5′-ATAAGATTACAGTTGTTGGGGTTGGTG-3′ (SEQ ID NO: 147)5′-AGAUUACAGUUGUUGGGGUUGGUgc-3′ (SEQ ID NO: 4)3′-AUUCUAAUGUCAACAACCCCAACCACG-5′ (SEQ ID NO: 76) LDHA-361 Target:5′-TAAGATTACAGTTGTTGGGGTTGGTGC-3′ (SEQ ID NO: 148)5′-GAUUACAGUUGUUGGGGUUGGUGct-3′ (SEQ ID NO: 5)3′-UUCUAAUGUCAACAACCCCAACCACGA-5′ (SEQ ID NO: 77) LDHA-362 Target:5′-AAGATTACAGTTGTTGGGGTTGGTGCT-3′ (SEQ ID NO: 149)5′-AUUACAGUUGUUGGGGUUGGUGCtg-3′ (SEQ ID NO: 6)3′-UCUAAUGUCAACAACCCCAACCACGAC-5′ (SEQ ID NO: 78) LDHA-363 Target:5′-AGATTACAGTTGTTGGGGTTGGTGCTG-3′ (SEQ ID NO: 150)5′-UUACAGUUGUUGGGGUUGGUGCUgt-3′ (SEQ ID NO: 7)3′-CUAAUGUCAACAACCCCAACCACGACA-5′ (SEQ ID NO: 79) LDHA-364 Target:5′-GATTACAGTTGTTGGGGTTGGTGCTGT-3′ (SEQ ID NO: 151)5′-UACAGUUGUUGGGGUUGGUGCUGtt-3′ (SEQ ID NO: 8)3′-UAAUGUCAACAACCCCAACCACGACAA-5′ (SEQ ID NO: 80) LDHA-365 Target:5′-ATTACAGTTGTTGGGGTTGGTGCTGTT-3′ (SEQ ID NO: 152)5′-ACAGUUGUUGGGGUUGGUGCUGUtg-3′ (SEQ ID NO: 9)3′-AAUGUCAACAACCCCAACCACGACAAC-5′ (SEQ ID NO: 81) LDHA-366 Target:5′-TTACAGTTGTTGGGGTTGGTGCTGTTG-3′ (SEQ ID NO: 153)5′-CAGUUGUUGGGGUUGGUGCUGUUgg-3′ (SEQ ID NO: 10)3′-AUGUCAACAACCCCAACCACGACAACC-5′ (SEQ ID NO: 82) LDHA-367 Target:5′-TACAGTTGTTGGGGTTGGTGCTGTTGG-3′ (SEQ ID NO: 154)5′-GUUGUUGGGGUUGGUGCUGUUGGca-3′ (SEQ ID NO: 11)3′-GUCAACAACCCCAACCACGACAACCGU-5′ (SEQ ID NO: 83) LDHA-369 Target:5′-CAGTTGTTGGGGTTGGTGCTGTTGGCA-3′ (SEQ ID NO: 155)5′-UUGUUGGGGUUGGUGCUGUUGGCat-3′ (SEQ ID NO: 12)3′-UCAACAACCCCAACCACGACAACCGUA-5′ (SEQ ID NO: 84) LDHA-370 Target:5′-AGTTGTTGGGGTTGGTGCTGTTGGCAT-3′ (SEQ ID NO: 156)5′-CCUGUGCCAUCAGUAUCUUAAUGaa-3′ (SEQ ID NO: 13)3′-CCGGACACGGUAGUCAUAGAAUUACUU-5′ (SEQ ID NO: 85) LDHA-397 Target:5′-GGCCTGTGCCATCAGTATCTTAATGAA-3′ (SEQ ID NO: 157)5′-CUGUGCCAUCAGUAUCUUAAUGAag-3′ (SEQ ID NO: 14)3′-CGGACACGGUAGUCAUAGAAUUACUUC-5′ (SEQ ID NO: 86) LDHA-398 Target:5′-GCCTGTGCCATCAGTATCTTAATGAAG-3′ (SEQ ID NO: 158)5′-UGUGCCAUCAGUAUCUUAAUGAAgg-3′ (SEQ ID NO: 15)3′-GGACACGGUAGUCAUAGAAUUACUUCC-5′ (SEQ ID NO: 87) LDHA-399 Target:5′-CCTGTGCCATCAGTATCTTAATGAAGG-3′ (SEQ ID NO: 159)5′-GUGCCAUCAGUAUCUUAAUGAAGga-3′ (SEQ ID NO: 16)3′-GACACGGUAGUCAUAGAAUUACUUCCU-5′ (SEQ ID NO: 88) LDHA-400 Target:5′-CTGTGCCATCAGTATCTTAATGAAGGA-3′ (SEQ ID NO: 160)5′-UGCCAUCAGUAUCUUAAUGAAGGac-3′ (SEQ ID NO: 17)3′-ACACGGUAGUCAUAGAAUUACUUCCUG-5′ (SEQ ID NO: 89) LDHA-401 Target:5′-TGTGCCATCAGTATCTTAATGAAGGAC-3′ (SEQ ID NO: 161)5′-GCCAUCAGUAUCUUAAUGAAGGAct-3′ (SEQ ID NO: 18)3′-CACGGUAGUCAUAGAAUUACUUCCUGA-5′ (SEQ ID NO: 90) LDHA-402 Target:5′-GTGCCATCAGTATCTTAATGAAGGACT-3′ (SEQ ID NO: 162)5′-CCAUCAGUAUCUUAAUGAAGGACtt-3′ (SEQ ID NO: 19)3′-ACGGUAGUCAUAGAAUUACUUCCUGAA-5′ (SEQ ID NO: 91) LDHA-403 Target:5′-TGCCATCAGTATCTTAATGAAGGACTT-3′ (SEQ ID NO: 163)5′-CAUCAGUAUCUUAAUGAAGGACUtg-3′ (SEQ ID NO: 20)3′-CGGUAGUCAUAGAAUUACUUCCUGAAC-5′ (SEQ ID NO: 92) LDHA-404 Target:5′-GCCATCAGTATCTTAATGAAGGACTTG-3′ (SEQ ID NO: 164)5′-GUGGAUAUCUUGACCUACGUGGCtt-3′ (SEQ ID NO: 21)3′-GUCACCUAUAGAACUGGAUGCACCGAA-5′ (SEQ ID NO: 93) LDHA-714 Target:5′-CAGTGGATATCTTGACCTACGTGGCTT-3′ (SEQ ID NO: 165)5′-GAUAUCUUGACCUACGUGGCUUGga-3′ (SEQ ID NO: 22)3′-ACCUAUAGAACUGGAUGCACCGAACCU-5′ (SEQ ID NO: 94) LDHA-717 Target:5′-TGGATATCTTGACCTACGTGGCTTGGA-3′ (SEQ ID NO: 166)5′-AUAUCUUGACCUACGUGGCUUGGaa-3′ (SEQ ID NO: 23)3′-CCUAUAGAACUGGAUGCACCGAACCUU-5′ (SEQ ID NO: 95) LDHA-718 Target:5′-GGATATCTTGACCTACGTGGCTTGGAA-3′ (SEQ ID NO: 167)5′-UAUCUUGACCUACGUGGCUUGGAag-3′ (SEQ ID NO: 24)3′-CUAUAGAACUGGAUGCACCGAACCUUC-5′ (SEQ ID NO: 96) LDHA-719 Target:5′-GATATCTTGACCTACGTGGCTTGGAAG-3′ (SEQ ID NO: 168)5′-AUCUUGACCUACGUGGCUUGGAAga-3′ (SEQ ID NO: 25)3′-UAUAGAACUGGAUGCACCGAACCUUCU-5′ (SEQ ID NO: 97) LDHA-720 Target:5′-ATATCTTGACCTACGTGGCTTGGAAGA-3′ (SEQ ID NO: 169)5′-CUUGACCUACGUGGCUUGGAAGAta-3′ (SEQ ID NO: 26)3′-UAGAACUGGAUGCACCGAACCUUCUAU-5′ (SEQ ID NO: 98) LDHA-722 Target:5′-ATCTTGACCTACGTGGCTTGGAAGATA-3′ (SEQ ID NO: 170)5′-UUGACCUACGUGGCUUGGAAGAUaa-3′ (SEQ ID NO: 27)3′-AGAACUGGAUGCACCGAACCUUCUAUU-5′ (SEQ ID NO: 99) LDHA-723 Target:5′-TCTTGACCTACGTGGCTTGGAAGATAA-3′ (SEQ ID NO: 171)5′-UGACCUACGUGGCUUGGAAGAUAag-3′ (SEQ ID NO: 28)3′-GAACUGGAUGCACCGAACCUUCUAUUC-5′ (SEQ ID NO: 100) LDHA-724 Target:5′-CTTGACCTACGTGGCTTGGAAGATAAG-3′ (SEQ ID NO: 172)5′-GGAAGAUAAGUGGUUUUCCCAAAaa-3′ (SEQ ID NO: 29)3′-AACCUUCUAUUCACCAAAAGGGUUUUU-5′ (SEQ ID NO: 101) LDHA-739 Target:5′-TTGGAAGATAAGTGGTTTTCCCAAAAA-3′ (SEQ ID NO: 173)5′-GAAGAUAAGUGGUUUUCCCAAAAac-3′ (SEQ ID NO: 30)3′-ACCUUCUAUUCACCAAAAGGGUUUUUG-5′ (SEQ ID NO: 102) LDHA-740 Target:5′-TGGAAGATAAGTGGTTTTCCCAAAAAC-3′ (SEQ ID NO: 174)5′-CCUGUAUGGAGUGGAAUGAAUGUtg-3′ (SEQ ID NO: 31)3′-ACGGACAUACCUCACCUUACUUACAAC-5′ (SEQ ID NO: 103) LDHA-891 Target:5′-TGCCTGTATGGAGTGGAATGAATGTTG-3′ (SEQ ID NO: 175)5′-CUGUAUGGAGUGGAAUGAAUGUUgc-3′ (SEQ ID NO: 32)3′-CGGACAUACCUCACCUUACUUACAACG-5′ (SEQ ID NO: 104) LDHA-892 Target:5′-GCCTGTATGGAGTGGAATGAATGTTGC-3′ (SEQ ID NO: 176)5′-UGAAUGUUGCUGGUGUCUCUCUGaa-3′ (SEQ ID NO: 33)3′-UUACUUACAACGACCACAGAGAGACUU-5′ (SEQ ID NO: 105) LDHA-907 Target:5′-AATGAATGTTGCTGGTGTCTCTCTGAA-3′ (SEQ ID NO: 177)5′-GGACUGAUAAAGAUAAGGAACAGtg-3′ (SEQ ID NO: 34)3′-UCCCUGACUAUUUCUAUUCCUUGUCAC-5′ (SEQ ID NO: 106) LDHA-952 Target:5′-AGGGACTGATAAAGATAAGGAACAGTG-3′ (SEQ ID NO: 178)5′-GCAAUUUUAAAGUCUUCUGAUGUca-3′ (SEQ ID NO: 35)3′-GACGUUAAAAUUUCAGAAGACUACAGU-5′ (SEQ ID NO: 107) LDHA-1286 Target:5′-CTGCAATTTTAAAGTCTTCTGATGTCA-3′ (SEQ ID NO: 179)5′-CAAUUUUAAAGUCUUCUGAUGUCat-3′ (SEQ ID NO: 36)3′-ACGUUAAAAUUUCAGAAGACUACAGUA-5′ (SEQ ID NO: 108) LDHA-1287 Target:5′-TGCAATTTTAAAGTCTTCTGATGTCAT-3′ (SEQ ID NO: 180)5′-UUAAAGUCUUCUGAUGUCAUAUCat-3′ (SEQ ID NO: 37)3′-AAAAUUUCAGAAGACUACAGUAUAGUA-5′ (SEQ ID NO: 109) LDHA-1292 Target:5′-TTTTAAAGTCTTCTGATGTCATATCAT-3′ (SEQ ID NO: 181)5′-UAAAGUCUUCUGAUGUCAUAUCAtt-3′ (SEQ ID NO: 38)3′-AAAUUUCAGAAGACUACAGUAUAGUAA-5′ (SEQ ID NO: 110) LDHA-1293 Target:5′-TTTAAAGTCTTCTGATGTCATATCATT-3′ (SEQ ID NO: 182)5′-AAAGUCUUCUGAUGUCAUAUCAUtt-3′ (SEQ ID NO: 39)3′-AAUUUCAGAAGACUACAGUAUAGUAAA-5′ (SEQ ID NO: 111) LDHA-1294 Target:5′-TTAAAGTCTTCTGATGTCATATCATTT-3′ (SEQ ID NO: 183)5′-CAUGUUGUCCUUUUUAUCUGAUCtg-3′ (SEQ ID NO: 40)3′-ACGUACAACAGGAAAAAUAGACUAGAC-5′ (SEQ ID NO: 112) LDHA-1359 Target:5′-TGCATGTTGTCCTTTTTATCTGATCTG-3′ (SEQ ID NO: 184)5′-AUGUUGUCCUUUUUAUCUGAUCUgt-3′ (SEQ ID NO: 41)3′-CGUACAACAGGAAAAAUAGACUAGACA-5′ (SEQ ID NO: 113) LDHA-1360 Target:5′-GCATGTTGTCCTTTTTATCTGATCTGT-3′ (SEQ ID NO: 185)5′-UGUUGUCCUUUUUAUCUGAUCUGtg-3′ (SEQ ID NO: 42)3′-GUACAACAGGAAAAAUAGACUAGACAC-5′ (SEQ ID NO: 114) LDHA-1361 Target:5′-CATGTTGTCCTTTTTATCTGATCTGTG-3′ (SEQ ID NO: 186)5′-GUUGUCCUUUUUAUCUGAUCUGUga-3′ (SEQ ID NO: 43)3′-UACAACAGGAAAAAUAGACUAGACACU-5′ (SEQ ID NO: 115) LDHA-1362 Target:5′-ATGTTGTCCTTTTTATCTGATCTGTGA-3′ (SEQ ID NO: 187)5′-UUGUCCUUUUUAUCUGAUCUGUGat-3′ (SEQ ID NO: 44)3′-ACAACAGGAAAAAUAGACUAGACACUA-5′ (SEQ ID NO: 116) LDHA-1363 Target:5′-TGTTGTCCTTTTTATCTGATCTGTGAT-3′ (SEQ ID NO: 188)5′-GUCCUUUUUAUCUGAUCUGUGAUta-3′ (SEQ ID NO: 45)3′-AACAGGAAAAAUAGACUAGACACUAAU-5′ (SEQ ID NO: 117) LDHA-1365 Target:5′-TTGTCCTTTTTATCTGATCTGTGATTA-3′ (SEQ ID NO: 189)5′-UCCUUUUUAUCUGAUCUGUGAUUaa-3′ (SEQ ID NO: 46)3′-ACAGGAAAAAUAGACUAGACACUAAUU-5′ (SEQ ID NO: 118) LDHA-1366 Target:5′-TGTCCTTTTTATCTGATCTGTGATTAA-3′ (SEQ ID NO: 190)5′-CCUUUUUAUCUGAUCUGUGAUUAaa-3′ (SEQ ID NO: 47)3′-CAGGAAAAAUAGACUAGACACUAAUUU-5′ (SEQ ID NO: 119) LDHA-1367 Target:5′-GTCCTTTTTATCTGATCTGTGATTAAA-3′ (SEQ ID NO: 191)5′-CUUUUUAUCUGAUCUGUGAUUAAag-3′ (SEQ ID NO: 48)3′-AGGAAAAAUAGACUAGACACUAAUUUC-5′ (SEQ ID NO: 120) LDHA-1368 Target:5′-TCCTTTTTATCTGATCTGTGATTAAAG-3′ (SEQ ID NO: 192)5′-UUUUAUCUGAUCUGUGAUUAAAGca-3′ (SEQ ID NO: 49)3′-GAAAAAUAGACUAGACACUAAUUUCGU-5′ (SEQ ID NO: 121) LDHA-1370 Target:5′-CTTTTTATCTGATCTGTGATTAAAGCA-3′ (SEQ ID NO: 193)5′-UUUAUCUGAUCUGUGAUUAAAGCag-3′ (SEQ ID NO: 50)3′-AAAAAUAGACUAGACACUAAUUUCGUC-5′ (SEQ ID NO: 122) LDHA-1371 Target:5′-TTTTTATCTGATCTGTGATTAAAGCAG-3′ (SEQ ID NO: 194)5′-UUAUCUGAUCUGUGAUUAAAGCAgt-3′ (SEQ ID NO: 51)3′-AAAAUAGACUAGACACUAAUUUCGUCA-5′ (SEQ ID NO: 123) LDHA-1372 Target:5′-TTTTATCTGATCTGTGATTAAAGCAGT-3′ (SEQ ID NO: 195)5′-CAGUAAUAUUUUAAGAUGGACUGgg-3′ (SEQ ID NO: 52)3′-UCGUCAUUAUAAAAUUCUACCUGACCC-5′ (SEQ ID NO: 124) LDHA-1393 Target:5′-AGCAGTAATATTTTAAGATGGACTGGG-3′ (SEQ ID NO: 196)5′-AACUCCUGAAGUUAGAAAUAAGAat-3′ (SEQ ID NO: 53)3′-AGUUGAGGACUUCAAUCUUUAUUCUUA-5′ (SEQ ID NO: 125) LDHA-1427 Target:5′-TCAACTCCTGAAGTTAGAAATAAGAAT-3′ (SEQ ID NO: 197)5′-ACUCCUGAAGUUAGAAAUAAGAAtg-3′ (SEQ ID NO: 54)3′-GUUGAGGACUUCAAUCUUUAUUCUUAC-5′ (SEQ ID NO: 126) LDHA-1428 Target:5′-CAACTCCTGAAGTTAGAAATAAGAATG-3′ (SEQ ID NO: 198)5′-AACUGGUUAGUGUGAAAUAGUUCtg-3′ (SEQ ID NO: 55)3′-AGUUGACCAAUCACACUUUAUCAAGAC-5′ (SEQ ID NO: 127) LDHA-1512 Target:5′-TCAACTGGTTAGTGTGAAATAGTTCTG-3′ (SEQ ID NO: 199)5′-ACUGGUUAGUGUGAAAUAGUUCUgc-3′ (SEQ ID NO: 56)3′-GUUGACCAAUCACACUUUAUCAAGACG-5′ (SEQ ID NO: 128) LDHA-1513 Target:5′-CAACTGGTTAGTGTGAAATAGTTCTGC-3′ (SEQ ID NO: 200)5′-CUGGUUAGUGUGAAAUAGUUCUGcc-3′ (SEQ ID NO: 57)3′-UUGACCAAUCACACUUUAUCAAGACGG-5′ (SEQ ID NO: 129) LDHA-1514 Target:5′-AACTGGTTAGTGTGAAATAGTTCTGCC-3′ (SEQ ID NO: 201)5′-GGUUAGUGUGAAAUAGUUCUGCCac-3′ (SEQ ID NO: 58)3′-GACCAAUCACACUUUAUCAAGACGGUG-5′ (SEQ ID NO: 130) LDHA-1516 Target:5′-CTGGTTAGTGTGAAATAGTTCTGCCAC-3′ (SEQ ID NO: 202)5′-AUCCAGUGUAUAAAUCCAAUAUCat-3′ (SEQ ID NO: 59)3′-CCUAGGUCACAUAUUUAGGUUAUAGUA-5′ (SEQ ID NO: 131) LDHA-1684 Target:5′-GGATCCAGTGTATAAATCCAATATCAT-3′ (SEQ ID NO: 203)5′-AGUGUAUAAAUCCAAUAUCAUGUct-3′ (SEQ ID NO: 60)3′-GGUCACAUAUUUAGGUUAUAGUACAGA-5′ (SEQ ID NO: 132) LDHA-1688 Target:5′-CCAGTGTATAAATCCAATATCATGTCT-3′ (SEQ ID NO: 204)5′-CUUAUUUUGUGAACUAUAUCAGUag-3′ (SEQ ID NO: 61)3′-UAGAAUAAAACACUUGAUAUAGUCAUC-5′ (SEQ ID NO: 133) LDHA-1736 Target:5′-ATCTTATTTTGTGAACTATATCAGTAG-3′ (SEQ ID NO: 205)5′-UAUAUCAGUAGUGUACAUUACCAta-3′ (SEQ ID NO: 62)3′-UGAUAUAGUCAUCACAUGUAAUGGUAU-5′ (SEQ ID NO: 134) LDHA-1750 Target:5′-ACTATATCAGTAGTGTACATTACCATA-3′ (SEQ ID NO: 206)5′-AUCAGUAGUGUACAUUACCAUAUaa-3′ (SEQ ID NO: 63)3′-UAUAGUCAUCACAUGUAAUGGUAUAUU-5′ (SEQ ID NO: 135) LDHA-1753 Target:5′-ATATCAGTAGTGTACATTACCATATAA-3′ (SEQ ID NO: 207)5′-UCAGUAGUGUACAUUACCAUAUAat-3′ (SEQ ID NO: 64)3′-AUAGUCAUCACAUGUAAUGGUAUAUUA-5′ (SEQ ID NO: 136) LDHA-1754 Target:5′-TATCAGTAGTGTACATTACCATATAAT-3′ (SEQ ID NO: 208)5′-CAACCAACUAUCCAAGUGUUAUAcc-3′ (SEQ ID NO: 65)3′-ACGUUGGUUGAUAGGUUCACAAUAUGG-5′ (SEQ ID NO: 137) LDHA-1805 Target:5′-TGCAACCAACTATCCAAGTGTTATACC-3′ (SEQ ID NO: 209)5′-AACCAACUAUCCAAGUGUUAUACca-3′ (SEQ ID NO: 66)3′-CGUUGGUUGAUAGGUUCACAAUAUGGU-5′ (SEQ ID NO: 138) LDHA-1806 Target:5′-GCAACCAACTATCCAAGTGTTATACCA-3′ (SEQ ID NO: 210)5′-ACCAACUAUCCAAGUGUUAUACCaa-3′ (SEQ ID NO: 67)3′-GUUGGUUGAUAGGUUCACAAUAUGGUU-5′ (SEQ ID NO: 139) LDHA-1807 Target:5′-CAACCAACTATCCAAGTGTTATACCAA-3′ (SEQ ID NO: 211)5′-CCAACUAUCCAAGUGUUAUACCAac-3′ (SEQ ID NO: 68)3′-UUGGUUGAUAGGUUCACAAUAUGGUUG-5′ (SEQ ID NO: 140) LDHA-1808 Target:5′-AACCAACTATCCAAGTGTTATACCAAC-3′ (SEQ ID NO: 212)5′-ACUAUCCAAGUGUUAUACCAACUaa-3′ (SEQ ID NO: 69)3′-GUUGAUAGGUUCACAAUAUGGUUGAUU-5′ (SEQ ID NO: 141) LDHA-1811 Target:5′-CAACTATCCAAGTGTTATACCAACTAA-3′ (SEQ ID NO: 213)5′-CUAUCCAAGUGUUAUACCAACUAaa-3′ (SEQ ID NO: 70)3′-UUGAUAGGUUCACAAUAUGGUUGAUUU-5′ (SEQ ID NO: 142) LDHA-1812 Target:5′-AACTATCCAAGTGTTATACCAACTAAA-3′ (SEQ ID NO: 214)5′-UCCAAGUGUUAUACCAACUAAAAcc-3′ (SEQ ID NO: 71)3′-AUAGGUUCACAAUAUGGUUGAUUUUGG-5′ (SEQ ID NO: 143) LDHA-1815 Target:5′-TATCCAAGTGTTATACCAACTAAAACC-3′ (SEQ ID NO: 215)5′-CCAAGUGUUAUACCAACUAAAACcc-3′ (SEQ ID NO: 72)3′-UAGGUUCACAAUAUGGUUGAUUUUGGG-5′ (SEQ ID NO: 144) LDHA-1816 Target:5′-ATCCAAGTGTTATACCAACTAAAACCC-3′ (SEQ ID NO: 216)

TABLE 3 Selected Human Anti-Lactate Dehydrogenase DsiRNAs, UnmodifiedDuplexes (Asymmetrics) 5′-AGAAUAAGAUUACAGUUGUUGGGGU-3′ (SEQ ID NO: 217)3′-GGUCUUAUUCUAAUGUCAACAACCCCA-5′ (SEQ ID NO: 73) LDHA-355 Target:5′-CCAGAATAAGATTACAGTTGTTGGGGT-3′ (SEQ ID NO: 145)5′-GAAUAAGAUUACAGUUGUUGGGGUU-3′ (SEQ ID NO: 218)3′-GUCUUAUUCUAAUGUCAACAACCCCAA-5′ (SEQ ID NO: 74) LDHA-356 Target:5′-CAGAATAAGATTACAGTTGTTGGGGTT-3′ (SEQ ID NO: 146)5′-AAGAUUACAGUUGUUGGGGUUGGUG-3′ (SEQ ID NO: 219)3′-UAUUCUAAUGUCAACAACCCCAACCAC-5′ (SEQ ID NO: 75) LDHA-360 Target:5′-ATAAGATTACAGTTGTTGGGGTTGGTG-3′ (SEQ ID NO: 147)5′-AGAUUACAGUUGUUGGGGUUGGUGC-3′ (SEQ ID NO: 220)3′-AUUCUAAUGUCAACAACCCCAACCACG-5′ (SEQ ID NO: 76) LDHA-361 Target:5′-TAAGATTACAGTTGTTGGGGTTGGTGC-3′ (SEQ ID NO: 148)5′-GAUUACAGUUGUUGGGGUUGGUGCU-3′ (SEQ ID NO: 221)3′-UUCUAAUGUCAACAACCCCAACCACGA-5′ (SEQ ID NO: 77) LDHA-362 Target:5′-AAGATTACAGTTGTTGGGGTTGGTGCT-3′ (SEQ ID NO: 149)5′-AUUACAGUUGUUGGGGUUGGUGCUG-3′ (SEQ ID NO: 222)3′-UCUAAUGUCAACAACCCCAACCACGAC-5′ (SEQ ID NO: 78) LDHA-363 Target:5′-AGATTACAGTTGTTGGGGTTGGTGCTG-3′ (SEQ ID NO: 150)5′-UUACAGUUGUUGGGGUUGGUGCUGU-3′ (SEQ ID NO: 223)3′-CUAAUGUCAACAACCCCAACCACGACA-5′ (SEQ ID NO: 79) LDHA-364 Target:5′-GATTACAGTTGTTGGGGTTGGTGCTGT-3′ (SEQ ID NO: 151)5′-UACAGUUGUUGGGGUUGGUGCUGUU-3′ (SEQ ID NO: 224)3′-UAAUGUCAACAACCCCAACCACGACAA-5′ (SEQ ID NO: 80) LDHA-365 Target:5′-ATTACAGTTGTTGGGGTTGGTGCTGTT-3′ (SEQ ID NO: 152)5′-ACAGUUGUUGGGGUUGGUGCUGUUG-3′ (SEQ ID NO: 225)3′-AAUGUCAACAACCCCAACCACGACAAC-5′ (SEQ ID NO: 81) LDHA-366 Target:5′-TTACAGTTGTTGGGGTTGGTGCTGTTG-3′ (SEQ ID NO: 153)5′-CAGUUGUUGGGGUUGGUGCUGUUGG-3′ (SEQ ID NO: 226)3′-AUGUCAACAACCCCAACCACGACAACC-5′ (SEQ ID NO: 82) LDHA-367 Target:5′-TACAGTTGTTGGGGTTGGTGCTGTTGG-3′ (SEQ ID NO: 154)5′-GUUGUUGGGGUUGGUGCUGUUGGCA-3′ (SEQ ID NO: 227)3′-GUCAACAACCCCAACCACGACAACCGU-5′ (SEQ ID NO: 83) LDHA-369 Target:5′-CAGTTGTTGGGGTTGGTGCTGTTGGCA-3′ (SEQ ID NO: 155)5′-UUGUUGGGGUUGGUGCUGUUGGCAU-3′ (SEQ ID NO: 228)3′-UCAACAACCCCAACCACGACAACCGUA-5′ (SEQ ID NO: 84) LDHA-370 Target:5′-AGTTGTTGGGGTTGGTGCTGTTGGCAT-3′ (SEQ ID NO: 156)5′-CCUGUGCCAUCAGUAUCUUAAUGAA-3′ (SEQ ID NO: 229)3′-CCGGACACGGUAGUCAUAGAAUUACUU-5′ (SEQ ID NO: 85) LDHA-397 Target:5′-GGCCTGTGCCATCAGTATCTTAATGAA-3′ (SEQ ID NO: 157)5′-CUGUGCCAUCAGUAUCUUAAUGAAG-3′ (SEQ ID NO: 230)3′-CGGACACGGUAGUCAUAGAAUUACUUC-5′ (SEQ ID NO: 86) LDHA-398 Target:5′-GCCTGTGCCATCAGTATCTTAATGAAG-3′ (SEQ ID NO: 158)5′-UGUGCCAUCAGUAUCUUAAUGAAGG-3′ (SEQ ID NO: 231)3′-GGACACGGUAGUCAUAGAAUUACUUCC-5′ (SEQ ID NO: 87) LDHA-399 Target:5′-CCTGTGCCATCAGTATCTTAATGAAGG-3′ (SEQ ID NO: 159)5′-GUGCCAUCAGUAUCUUAAUGAAGGA-3′ (SEQ ID NO: 232)3′-GACACGGUAGUCAUAGAAUUACUUCCU-5′ (SEQ ID NO: 88) LDHA-400 Target:5′-CTGTGCCATCAGTATCTTAATGAAGGA-3′ (SEQ ID NO: 160)5′-UGCCAUCAGUAUCUUAAUGAAGGAC-3′ (SEQ ID NO: 233)3′-ACACGGUAGUCAUAGAAUUACUUCCUG-5′ (SEQ ID NO: 89) LDHA-401 Target:5′-TGTGCCATCAGTATCTTAATGAAGGAC-3′ (SEQ ID NO: 161)5′-GCCAUCAGUAUCUUAAUGAAGGACU-3′ (SEQ ID NO: 234)3′-CACGGUAGUCAUAGAAUUACUUCCUGA-5′ (SEQ ID NO: 90) LDHA-402 Target:5′-GTGCCATCAGTATCTTAATGAAGGACT-3′ (SEQ ID NO: 162)5′-CCAUCAGUAUCUUAAUGAAGGACUU-3′ (SEQ ID NO: 235)3′-ACGGUAGUCAUAGAAUUACUUCCUGAA-5′ (SEQ ID NO: 91) LDHA-403 Target:5′-TGCCATCAGTATCTTAATGAAGGACTT-3′ (SEQ ID NO: 163)5′-CAUCAGUAUCUUAAUGAAGGACUUG-3′ (SEQ ID NO: 236)3′-CGGUAGUCAUAGAAUUACUUCCUGAAC-5′ (SEQ ID NO: 92) LDHA-404 Target:5′-GCCATCAGTATCTTAATGAAGGACTTG-3′ (SEQ ID NO: 164)5′-GUGGAUAUCUUGACCUACGUGGCUU-3′ (SEQ ID NO: 237)3′-GUCACCUAUAGAACUGGAUGCACCGAA-5′ (SEQ ID NO: 93) LDHA-714 Target:5′-CAGTGGATATCTTGACCTACGTGGCTT-3′ (SEQ ID NO: 165)5′-GAUAUCUUGACCUACGUGGCUUGGA-3′ (SEQ ID NO: 238)3′-ACCUAUAGAACUGGAUGCACCGAACCU-5′ (SEQ ID NO: 94) LDHA-717 Target:5′-TGGATATCTTGACCTACGTGGCTTGGA-3′ (SEQ ID NO: 166)5′-AUAUCUUGACCUACGUGGCUUGGAA-3′ (SEQ ID NO: 239)3′-CCUAUAGAACUGGAUGCACCGAACCUU-5′ (SEQ ID NO: 95) LDHA-718 Target:5′-GGATATCTTGACCTACGTGGCTTGGAA-3′ (SEQ ID NO: 167)5′-UAUCUUGACCUACGUGGCUUGGAAG-3′ (SEQ ID NO: 240)3′-CUAUAGAACUGGAUGCACCGAACCUUC-5′ (SEQ ID NO: 96) LDHA-719 Target:5′-GATATCTTGACCTACGTGGCTTGGAAG-3′ (SEQ ID NO: 168)5′-AUCUUGACCUACGUGGCUUGGAAGA-3′ (SEQ ID NO: 241)3′-UAUAGAACUGGAUGCACCGAACCUUCU-5′ (SEQ ID NO: 97) LDHA-720 Target:5′-ATATCTTGACCTACGTGGCTTGGAAGA-3′ (SEQ ID NO: 169)5′-CUUGACCUACGUGGCUUGGAAGAUA-3′ (SEQ ID NO: 242)3′-UAGAACUGGAUGCACCGAACCUUCUAU-5′ (SEQ ID NO: 98) LDHA-722 Target:5′-ATCTTGACCTACGTGGCTTGGAAGATA-3′ (SEQ ID NO: 170)5′-UUGACCUACGUGGCUUGGAAGAUAA-3′ (SEQ ID NO: 243)3′-AGAACUGGAUGCACCGAACCUUCUAUU-5′ (SEQ ID NO: 99) LDHA-723 Target:5′-TCTTGACCTACGTGGCTTGGAAGATAA-3′ (SEQ ID NO: 171)5′-UGACCUACGUGGCUUGGAAGAUAAG-3′ (SEQ ID NO: 244)3′-GAACUGGAUGCACCGAACCUUCUAUUC-5′ (SEQ ID NO: 100) LDHA-724 Target:5′-CTTGACCTACGTGGCTTGGAAGATAAG-3′ (SEQ ID NO: 172)5′-GGAAGAUAAGUGGUUUUCCCAAAAA-3′ (SEQ ID NO: 245)3′-AACCUUCUAUUCACCAAAAGGGUUUUU-5′ (SEQ ID NO: 101) LDHA-739 Target:5′-TTGGAAGATAAGTGGTTTTCCCAAAAA-3′ (SEQ ID NO: 173)5′-GAAGAUAAGUGGUUUUCCCAAAAAC-3′ (SEQ ID NO: 246)3′-ACCUUCUAUUCACCAAAAGGGUUUUUG-5′ (SEQ ID NO: 102) LDHA-740 Target:5′-TGGAAGATAAGTGGTTTTCCCAAAAAC-3′ (SEQ ID NO: 174)5′-CCUGUAUGGAGUGGAAUGAAUGUUG-3′ (SEQ ID NO: 247)3′-ACGGACAUACCUCACCUUACUUACAAC-5′ (SEQ ID NO: 103) LDHA-891 Target:5′-TGCCTGTATGGAGTGGAATGAATGTTG-3′ (SEQ ID NO: 175)5′-CUGUAUGGAGUGGAAUGAAUGUUGC-3′ (SEQ ID NO: 248)3′-CGGACAUACCUCACCUUACUUACAACG-5′ (SEQ ID NO: 104) LDHA-892 Target:5′-GCCTGTATGGAGTGGAATGAATGTTGC-3′ (SEQ ID NO: 176)5′-UGAAUGUUGCUGGUGUCUCUCUGAA-3′ (SEQ ID NO: 249)3′-UUACUUACAACGACCACAGAGAGACUU-5′ (SEQ ID NO: 105) LDHA-907 Target:5′-AATGAATGTTGCTGGTGTCTCTCTGAA-3′ (SEQ ID NO: 177)5′-GGACUGAUAAAGAUAAGGAACAGUG-3′ (SEQ ID NO: 250)3′-UCCCUGACUAUUUCUAUUCCUUGUCAC-5′ (SEQ ID NO: 106) LDHA-952 Target:5′-AGGGACTGATAAAGATAAGGAACAGTG-3′ (SEQ ID NO: 178)5′-GCAAUUUUAAAGUCUUCUGAUGUCA-3′ (SEQ ID NO: 251)3′-GACGUUAAAAUUUCAGAAGACUACAGU-5′ (SEQ ID NO: 107) LDHA-1286 Target:5′-CTGCAATTTTAAAGTCTTCTGATGTCA-3′ (SEQ ID NO: 179)5′-CAAUUUUAAAGUCUUCUGAUGUCAU-3′ (SEQ ID NO: 252)3′-ACGUUAAAAUUUCAGAAGACUACAGUA-5′ (SEQ ID NO: 108) LDHA-1287 Target:5′-TGCAATTTTAAAGTCTTCTGATGTCAT-3′ (SEQ ID NO: 180)5′-UUAAAGUCUUCUGAUGUCAUAUCAU-3′ (SEQ ID NO: 253)3′-AAAAUUUCAGAAGACUACAGUAUAGUA-5′ (SEQ ID NO: 109) LDHA-1292 Target:5′-TTTTAAAGTCTTCTGATGTCATATCAT-3′ (SEQ ID NO: 181)5′-UAAAGUCUUCUGAUGUCAUAUCAUU-3′ (SEQ ID NO: 254)3′-AAAUUUCAGAAGACUACAGUAUAGUAA-5′ (SEQ ID NO: 110) LDHA-1293 Target:5′-TTTAAAGTCTTCTGATGTCATATCATT-3′ (SEQ ID NO: 182)5′-AAAGUCUUCUGAUGUCAUAUCAUUU-3′ (SEQ ID NO: 255)3′-AAUUUCAGAAGACUACAGUAUAGUAAA-5′ (SEQ ID NO: 111) LDHA-1294 Target:5′-TTAAAGTCTTCTGATGTCATATCATTT-3′ (SEQ ID NO: 183)5′-CAUGUUGUCCUUUUUAUCUGAUCUG-3′ (SEQ ID NO: 256)3′-ACGUACAACAGGAAAAAUAGACUAGAC-5′ (SEQ ID NO: 112) LDHA-1359 Target:5′-TGCATGTTGTCCTTTTTATCTGATCTG-3′ (SEQ ID NO: 184)5′-AUGUUGUCCUUUUUAUCUGAUCUGU-3′ (SEQ ID NO: 257)3′-CGUACAACAGGAAAAAUAGACUAGACA-5′ (SEQ ID NO: 113) LDHA-1360 Target:5′-GCATGTTGTCCTTTTTATCTGATCTGT-3′ (SEQ ID NO: 185)5′-UGUUGUCCUUUUUAUCUGAUCUGUG-3′ (SEQ ID NO: 258)3′-GUACAACAGGAAAAAUAGACUAGACAC-5′ (SEQ ID NO: 114) LDHA-1361 Target:5′-CATGTTGTCCTTTTTATCTGATCTGTG-3′ (SEQ ID NO: 186)5′-GUUGUCCUUUUUAUCUGAUCUGUGA-3′ (SEQ ID NO: 259)3′-UACAACAGGAAAAAUAGACUAGACACU-5′ (SEQ ID NO: 115) LDHA-1362 Target:5′-ATGTTGTCCTTTTTATCTGATCTGTGA-3′ (SEQ ID NO: 187)5′-UUGUCCUUUUUAUCUGAUCUGUGAU-3′ (SEQ ID NO: 260)3′-ACAACAGGAAAAAUAGACUAGACACUA-5′ (SEQ ID NO: 116) LDHA-1363 Target:5′-TGTTGTCCTTTTTATCTGATCTGTGAT-3′ (SEQ ID NO: 188)5′-GUCCUUUUUAUCUGAUCUGUGAUUA-3′ (SEQ ID NO: 261)3′-AACAGGAAAAAUAGACUAGACACUAAU-5′ (SEQ ID NO: 117) LDHA-1365 Target:5′-TTGTCCTTTTTATCTGATCTGTGATTA-3′ (SEQ ID NO: 189)5′-UCCUUUUUAUCUGAUCUGUGAUUAA-3′ (SEQ ID NO: 262)3′-ACAGGAAAAAUAGACUAGACACUAAUU-5′ (SEQ ID NO: 118) LDHA-1366 Target:5′-TGTCCTTTTTATCTGATCTGTGATTAA-3′ (SEQ ID NO: 190)5′-CCUUUUUAUCUGAUCUGUGAUUAAA-3′ (SEQ ID NO: 263)3′-CAGGAAAAAUAGACUAGACACUAAUUU-5′ (SEQ ID NO: 119) LDHA-1367 Target:5′-GTCCTTTTTATCTGATCTGTGATTAAA-3′ (SEQ ID NO: 191)5′-CUUUUUAUCUGAUCUGUGAUUAAAG-3′ (SEQ ID NO: 264)3′-AGGAAAAAUAGACUAGACACUAAUUUC-5′ (SEQ ID NO: 120) LDHA-1368 Target:5′-TCCTTTTTATCTGATCTGTGATTAAAG-3′ (SEQ ID NO: 192)5′-UUUUAUCUGAUCUGUGAUUAAAGCA-3′ (SEQ ID NO: 265)3′-GAAAAAUAGACUAGACACUAAUUUCGU-5′ (SEQ ID NO: 121) LDHA-1370 Target:5′-CTTTTTATCTGATCTGTGATTAAAGCA-3′ (SEQ ID NO: 193)5′-UUUAUCUGAUCUGUGAUUAAAGCAG-3′ (SEQ ID NO: 266)3′-AAAAAUAGACUAGACACUAAUUUCGUC-5′ (SEQ ID NO: 122) LDHA-1371 Target:5′-TTTTTATCTGATCTGTGATTAAAGCAG-3′ (SEQ ID NO: 194)5′-UUAUCUGAUCUGUGAUUAAAGCAGU-3′ (SEQ ID NO: 267)3′-AAAAUAGACUAGACACUAAUUUCGUCA-5′ (SEQ ID NO: 123) LDHA-1372 Target:5′-TTTTATCTGATCTGTGATTAAAGCAGT-3′ (SEQ ID NO: 195)5′-CAGUAAUAUUUUAAGAUGGACUGGG-3′ (SEQ ID NO: 268)3′-UCGUCAUUAUAAAAUUCUACCUGACCC-5′ (SEQ ID NO: 124) LDHA-1393 Target:5′-AGCAGTAATATTTTAAGATGGACTGGG-3′ (SEQ ID NO: 196)5′-AACUCCUGAAGUUAGAAAUAAGAAU-3′ (SEQ ID NO: 269)3′-AGUUGAGGACUUCAAUCUUUAUUCUUA-5′ (SEQ ID NO: 125) LDHA-1427 Target:5′-TCAACTCCTGAAGTTAGAAATAAGAAT-3′ (SEQ ID NO: 197)5′-ACUCCUGAAGUUAGAAAUAAGAAUG-3′ (SEQ ID NO: 270)3′-GUUGAGGACUUCAAUCUUUAUUCUUAC-5′ (SEQ ID NO: 126) LDHA-1428 Target:5′-CAACTCCTGAAGTTAGAAATAAGAATG-3′ (SEQ ID NO: 198)5′-AACUGGUUAGUGUGAAAUAGUUCUG-3′ (SEQ ID NO: 271)3′-AGUUGACCAAUCACACUUUAUCAAGAC-5′ (SEQ ID NO: 127) LDHA-1512 Target:5′-TCAACTGGTTAGTGTGAAATAGTTCTG-3′ (SEQ ID NO: 199)5′-ACUGGUUAGUGUGAAAUAGUUCUGC-3′ (SEQ ID NO: 272)3′-GUUGACCAAUCACACUUUAUCAAGACG-5′ (SEQ ID NO: 128) LDHA-1513 Target:5′-CAACTGGTTAGTGTGAAATAGTTCTGC-3′ (SEQ ID NO: 200)5′-CUGGUUAGUGUGAAAUAGUUCUGCC-3′ (SEQ ID NO: 273)3′-UUGACCAAUCACACUUUAUCAAGACGG-5′ (SEQ ID NO: 129) LDHA-1514 Target:5′-AACTGGTTAGTGTGAAATAGTTCTGCC-3′ (SEQ ID NO: 201)5′-GGUUAGUGUGAAAUAGUUCUGCCAC-3′ (SEQ ID NO: 274)3′-GACCAAUCACACUUUAUCAAGACGGUG-5′ (SEQ ID NO: 130) LDHA-1516 Target:5′-CTGGTTAGTGTGAAATAGTTCTGCCAC-3′ (SEQ ID NO: 202)5′-AUCCAGUGUAUAAAUCCAAUAUCAU-3′ (SEQ ID NO: 275)3′-CCUAGGUCACAUAUUUAGGUUAUAGUA-5′ (SEQ ID NO: 131) LDHA-1684 Target:5′-GGATCCAGTGTATAAATCCAATATCAT-3′ (SEQ ID NO: 203)5′-AGUGUAUAAAUCCAAUAUCAUGUCU-3′ (SEQ ID NO: 276)3′-GGUCACAUAUUUAGGUUAUAGUACAGA-5′ (SEQ ID NO: 132) LDHA-1688 Target:5′-CCAGTGTATAAATCCAATATCATGTCT-3′ (SEQ ID NO: 204)5′-CUUAUUUUGUGAACUAUAUCAGUAG-3′ (SEQ ID NO: 277)3′-UAGAAUAAAACACUUGAUAUAGUCAUC-5′ (SEQ ID NO: 133) LDHA-1736 Target:5′-ATCTTATTTTGTGAACTATATCAGTAG-3′ (SEQ ID NO: 205)5′-UAUAUCAGUAGUGUACAUUACCAUA-3′ (SEQ ID NO: 278)3′-UGAUAUAGUCAUCACAUGUAAUGGUAU-5′ (SEQ ID NO: 134) LDHA-1750 Target:5′-ACTATATCAGTAGTGTACATTACCATA-3′ (SEQ ID NO: 206)5′-AUCAGUAGUGUACAUUACCAUAUAA-3′ (SEQ ID NO: 279)3′-UAUAGUCAUCACAUGUAAUGGUAUAUU-5′ (SEQ ID NO: 135) LDHA-1753 Target:5′-ATATCAGTAGTGTACATTACCATATAA-3′ (SEQ ID NO: 207)5′-UCAGUAGUGUACAUUACCAUAUAAU-3′ (SEQ ID NO: 280)3′-AUAGUCAUCACAUGUAAUGGUAUAUUA-5′ (SEQ ID NO: 136) LDHA-1754 Target:5′-TATCAGTAGTGTACATTACCATATAAT-3′ (SEQ ID NO: 208)5′-CAACCAACUAUCCAAGUGUUAUACC-3′ (SEQ ID NO: 281)3′-ACGUUGGUUGAUAGGUUCACAAUAUGG-5′ (SEQ ID NO: 137) LDHA-1805 Target:5′-TGCAACCAACTATCCAAGTGTTATACC-3′ (SEQ ID NO: 209)5′-AACCAACUAUCCAAGUGUUAUACCA-3′ (SEQ ID NO: 282)3′-CGUUGGUUGAUAGGUUCACAAUAUGGU-5′ (SEQ ID NO: 138) LDHA-1806 Target:5′-GCAACCAACTATCCAAGTGTTATACCA-3′ (SEQ ID NO: 210)5′-ACCAACUAUCCAAGUGUUAUACCAA-3′ (SEQ ID NO: 283)3′-GUUGGUUGAUAGGUUCACAAUAUGGUU-5′ (SEQ ID NO: 139) LDHA-1807 Target:5′-CAACCAACTATCCAAGTGTTATACCAA-3′ (SEQ ID NO: 211)5′-CCAACUAUCCAAGUGUUAUACCAAC-3′ (SEQ ID NO: 284)3′-UUGGUUGAUAGGUUCACAAUAUGGUUG-5′ (SEQ ID NO: 140) LDHA-1808 Target:5′-AACCAACTATCCAAGTGTTATACCAAC-3′ (SEQ ID NO: 212)5′-ACUAUCCAAGUGUUAUACCAACUAA-3′ (SEQ ID NO: 285)3′-GUUGAUAGGUUCACAAUAUGGUUGAUU-5′ (SEQ ID NO: 141) LDHA-1811 Target:5′-CAACTATCCAAGTGTTATACCAACTAA-3′ (SEQ ID NO: 213)5′-CUAUCCAAGUGUUAUACCAACUAAA-3′ (SEQ ID NO: 286)3′-UUGAUAGGUUCACAAUAUGGUUGAUUU-5′ (SEQ ID NO: 142) LDHA-1812 Target:5′-AACTATCCAAGTGTTATACCAACTAAA-3′ (SEQ ID NO: 214)5′-UCCAAGUGUUAUACCAACUAAAACC-3′ (SEQ ID NO: 287)3′-AUAGGUUCACAAUAUGGUUGAUUUUGG-5′ (SEQ ID NO: 143) LDHA-1815 Target:5′-TATCCAAGTGTTATACCAACTAAAACC-3′ (SEQ ID NO: 215)5′-CCAAGUGUUAUACCAACUAAAACCC-3′ (SEQ ID NO: 288)3′-UAGGUUCACAAUAUGGUUGAUUUUGGG-5′ (SEQ ID NO: 144) LDHA-1816 Target:5′-ATCCAAGTGTTATACCAACTAAAACCC-3′ (SEQ ID NO: 216)

TABLE 4 DsiRNA Target Sequences (21mers) in Human Lactate DehydrogenasemRNA LDHA-355 21 nt Target: 5′-CCAGAAUAAGAUUACAGUUGU-3′ (SEQ ID NO: 289)LDHA-356 21 nt Target: 5′-CAGAAUAAGAUUACAGUUGUU-3′ (SEQ ID NO: 290)LDHA-360 21 nt Target: 5′-AUAAGAUUACAGUUGUUGGGG-3′ (SEQ ID NO: 291)LDHA-361 21 nt Target: 5′-UAAGAUUACAGUUGUUGGGGU-3′ (SEQ ID NO: 292)LDHA-362 21 nt Target: 5′-AAGAUUACAGUUGUUGGGGUU-3′ (SEQ ID NO: 293)LDHA-363 21 nt Target: 5′-AGAUUACAGUUGUUGGGGUUG-3′ (SEQ ID NO: 294)LDHA-364 21 nt Target: 5′-GAUUACAGUUGUUGGGGUUGG-3′ (SEQ ID NO: 295)LDHA-365 21 nt Target: 5′-AUUACAGUUGUUGGGGUUGGU-3′ (SEQ ID NO: 296)LDHA-366 21 nt Target: 5′-UUACAGUUGUUGGGGUUGGUG-3′ (SEQ ID NO: 297)LDHA-367 21 nt Target: 5′-UACAGUUGUUGGGGUUGGUGC-3′ (SEQ ID NO: 298)LDHA-369 21 nt Target: 5′-CAGUUGUUGGGGUUGGUGCUG-3′ (SEQ ID NO: 299)LDHA-370 21 nt Target: 5′-AGUUGUUGGGGUUGGUGCUGU-3′ (SEQ ID NO: 300)LDHA-397 21 nt Target: 5′-GGCCUGUGCCAUCAGUAUCUU-3′ (SEQ ID NO: 301)LDHA-398 21 nt Target: 5′-GCCUGUGCCAUCAGUAUCUUA-3′ (SEQ ID NO: 302)LDHA-399 21 nt Target: 5′-CCUGUGCCAUCAGUAUCUUAA-3′ (SEQ ID NO: 303)LDHA-400 21 nt Target: 5′-CUGUGCCAUCAGUAUCUUAAU-3′ (SEQ ID NO: 304)LDHA-401 21 nt Target: 5′-UGUGCCAUCAGUAUCUUAAUG-3′ (SEQ ID NO: 305)LDHA-402 21 nt Target: 5′-GUGCCAUCAGUAUCUUAAUGA-3′ (SEQ ID NO: 306)LDHA-403 21 nt Target: 5′-UGCCAUCAGUAUCUUAAUGAA-3′ (SEQ ID NO: 307)LDHA-404 21 nt Target: 5′-GCCAUCAGUAUCUUAAUGAAG-3′ (SEQ ID NO: 308)LDHA-714 21 nt Target: 5′-CAGUGGAUAUCUUGACCUACG-3′ (SEQ ID NO: 309)LDHA-717 21 nt Target: 5′-UGGAUAUCUUGACCUACGUGG-3′ (SEQ ID NO: 310)LDHA-718 21 nt Target: 5′-GGAUAUCUUGACCUACGUGGC-3′ (SEQ ID NO: 311)LDHA-719 21 nt Target: 5′-GAUAUCUUGACCUACGUGGCU-3′ (SEQ ID NO: 312)LDHA-720 21 nt Target: 5′-AUAUCUUGACCUACGUGGCUU-3′ (SEQ ID NO: 313)LDHA-722 21 nt Target: 5′-AUCUUGACCUACGUGGCUUGG-3′ (SEQ ID NO: 314)LDHA-723 21 nt Target: 5′-UCUUGACCUACGUGGCUUGGA-3′ (SEQ ID NO: 315)LDHA-724 21 nt Target: 5′-CUUGACCUACGUGGCUUGGAA-3′ (SEQ ID NO: 316)LDHA-739 21 nt Target: 5′-UUGGAAGAUAAGUGGUUUUCC-3′ (SEQ ID NO: 317)LDHA-740 21 nt Target: 5′-UGGAAGAUAAGUGGUUUUCCC-3′ (SEQ ID NO: 318)LDHA-891 21 nt Target: 5′-UGCCUGUAUGGAGUGGAAUGA-3′ (SEQ ID NO: 319)LDHA-892 21 nt Target: 5′-GCCUGUAUGGAGUGGAAUGAA-3′ (SEQ ID NO: 320)LDHA-907 21 nt Target: 5′-AAUGAAUGUUGCUGGUGUCUC-3′ (SEQ ID NO: 321)LDHA-952 21 nt Target: 5′-AGGGACUGAUAAAGAUAAGGA-3′ (SEQ ID NO: 322)LDHA-1286 21 nt Target: 5′-CUGCAAUUUUAAAGUCUUCUG-3′ (SEQ ID NO: 323)LDHA-1287 21 nt Target: 5′-UGCAAUUUUAAAGUCUUCUGA-3′ (SEQ ID NO: 324)LDHA-1292 21 nt Target: 5′-UUUUAAAGUCUUCUGAUGUCA-3′ (SEQ ID NO: 325)LDHA-1293 21 nt Target: 5′-UUUAAAGUCUUCUGAUGUCAU-3′ (SEQ ID NO: 326)LDHA-1294 21 nt Target: 5′-UUAAAGUCUUCUGAUGUCAUA-3′ (SEQ ID NO: 327)LDHA-1359 21 nt Target: 5′-UGCAUGUUGUCCUUUUUAUCU-3′ (SEQ ID NO: 328)LDHA-1360 21 nt Target: 5′-GCAUGUUGUCCUUUUUAUCUG-3′ (SEQ ID NO: 329)LDHA-1361 21 nt Target: 5′-CAUGUUGUCCUUUUUAUCUGA-3′ (SEQ ID NO: 330)LDHA-1362 21 nt Target: 5′-AUGUUGUCCUUUUUAUCUGAU-3′ (SEQ ID NO: 331)LDHA-1363 21 nt Target: 5′-UGUUGUCCUUUUUAUCUGAUC-3′ (SEQ ID NO: 332)LDHA-1365 21 nt Target: 5′-UUGUCCUUUUUAUCUGAUCUG-3′ (SEQ ID NO: 333)LDHA-1366 21 nt Target: 5′-UGUCCUUUUUAUCUGAUCUGU-3′ (SEQ ID NO: 334)LDHA-1367 21 nt Target: 5′-GUCCUUUUUAUCUGAUCUGUG-3′ (SEQ ID NO: 335)LDHA-1368 21 nt Target: 5′-UCCUUUUUAUCUGAUCUGUGA-3′ (SEQ ID NO: 336)LDHA-1370 21 nt Target: 5′-CUUUUUAUCUGAUCUGUGAUU-3′ (SEQ ID NO: 337)LDHA-1371 21 nt Target: 5′-UUUUUAUCUGAUCUGUGAUUA-3′ (SEQ ID NO: 338)LDHA-1372 21 nt Target: 5′-UUUUAUCUGAUCUGUGAUUAA-3′ (SEQ ID NO: 339)LDHA-1393 21 nt Target: 5′-AGCAGUAAUAUUUUAAGAUGG-3′ (SEQ ID NO: 340)LDHA-1427 21 nt Target: 5′-UCAACUCCUGAAGUUAGAAAU-3′ (SEQ ID NO: 341)LDHA-1428 21 nt Target: 5′-CAACUCCUGAAGUUAGAAAUA-3′ (SEQ ID NO: 342)LDHA-1512 21 nt Target: 5′-UCAACUGGUUAGUGUGAAAUA-3′ (SEQ ID NO: 343)LDHA-1513 21 nt Target: 5′-CAACUGGUUAGUGUGAAAUAG-3′ (SEQ ID NO: 344)LDHA-1514 21 nt Target: 5′-AACUGGUUAGUGUGAAAUAGU-3′ (SEQ ID NO: 345)LDHA-1516 21 nt Target: 5′-CUGGUUAGUGUGAAAUAGUUC-3′ (SEQ ID NO: 346)LDHA-1684 21 nt Target: 5′-GGAUCCAGUGUAUAAAUCCAA-3′ (SEQ ID NO: 347)LDHA-1688 21 nt Target: 5′-CCAGUGUAUAAAUCCAAUAUC-3′ (SEQ ID NO: 348)LDHA-1736 21 nt Target: 5′-AUCUUAUUUUGUGAACUAUAU-3′ (SEQ ID NO: 349)LDHA-1750 21 nt Target: 5′-ACUAUAUCAGUAGUGUACAUU-3′ (SEQ ID NO: 350)LDHA-1753 21 nt Target: 5′-AUAUCAGUAGUGUACAUUACC-3′ (SEQ ID NO: 351)LDHA-1754 21 nt Target: 5′-UAUCAGUAGUGUACAUUACCA-3′ (SEQ ID NO: 352)LDHA-1805 21 nt Target: 5′-UGCAACCAACUAUCCAAGUGU-3′ (SEQ ID NO: 353)LDHA-1806 21 nt Target: 5′-GCAACCAACUAUCCAAGUGUU-3′ (SEQ ID NO: 354)LDHA-1807 21 nt Target: 5′-CAACCAACUAUCCAAGUGUUA-3′ (SEQ ID NO: 355)LDHA-1808 21 nt Target: 5′-AACCAACUAUCCAAGUGUUAU-3′ (SEQ ID NO: 356)LDHA-1811 21 nt Target: 5′-CAACUAUCCAAGUGUUAUACC-3′ (SEQ ID NO: 357)LDHA-1812 21 nt Target: 5′-AACUAUCCAAGUGUUAUACCA-3′ (SEQ ID NO: 358)LDHA-1815 21 nt Target: 5′-UAUCCAAGUGUUAUACCAACU-3′ (SEQ ID NO: 359)LDHA-1816 21 nt Target: 5′-AUCCAAGUGUUAUACCAACUA-3′ (SEQ ID NO: 360)

TABLE 5 Selected Human Anti-Lactate Dehydrogenase “Blunt/Blunt” DsiRNAs5′-CCAGAAUAAGAUUACAGUUGUUGGGGU-3′ (SEQ ID NO: 361)3′-GGUCUUAUUCUAAUGUCAACAACCCCA-5′ (SEQ ID NO: 73) LDHA-355 Target:5′-CCAGAATAAGATTACAGTTGTTGGGGT-3′ (SEQ ID NO: 145)5′-CAGAAUAAGAUUACAGUUGUUGGGGUU-3′ (SEQ ID NO: 362)3′-GUCUUAUUCUAAUGUCAACAACCCCAA-5′ (SEQ ID NO: 74) LDHA-356 Target:5′-CAGAATAAGATTACAGTTGTTGGGGTT-3′ (SEQ ID NO: 146)5′-AUAAGAUUACAGUUGUUGGGGUUGGUG-3′ (SEQ ID NO: 363)3′-UAUUCUAAUGUCAACAACCCCAACCAC-5′ (SEQ ID NO: 75) LDHA-360 Target:5′-ATAAGATTACAGTTGTTGGGGTTGGTG-3′ (SEQ ID NO: 147)5′-UAAGAUUACAGUUGUUGGGGUUGGUGC-3′ (SEQ ID NO: 364)3′-AUUCUAAUGUCAACAACCCCAACCACG-5′ (SEQ ID NO: 76) LDHA-361 Target:5′-TAAGATTACAGTTGTTGGGGTTGGTGC-3′ (SEQ ID NO: 148)5′-AAGAUUACAGUUGUUGGGGUUGGUGCU-3′ (SEQ ID NO: 365)3′-UUCUAAUGUCAACAACCCCAACCACGA-5′ (SEQ ID NO: 77) LDHA-362 Target:5′-AAGATTACAGTTGTTGGGGTTGGTGCT-3′ (SEQ ID NO: 149)5′-AGAUUACAGUUGUUGGGGUUGGUGCUG-3′ (SEQ ID NO: 366)3′-UCUAAUGUCAACAACCCCAACCACGAC-5′ (SEQ ID NO: 78) LDHA-363 Target:5′-AGATTACAGTTGTTGGGGTTGGTGCTG-3′ (SEQ ID NO: 150)5′-GAUUACAGUUGUUGGGGUUGGUGCUGU-3′ (SEQ ID NO: 367)3′-CUAAUGUCAACAACCCCAACCACGACA-5′ (SEQ ID NO: 79) LDHA-364 Target:5′-GATTACAGTTGTTGGGGTTGGTGCTGT-3′ (SEQ ID NO: 151)5′-AUUACAGUUGUUGGGGUUGGUGCUGUU-3′ (SEQ ID NO: 368)3′-UAAUGUCAACAACCCCAACCACGACAA-5′ (SEQ ID NO: 80) LDHA-365 Target:5′-ATTACAGTTGTTGGGGTTGGTGCTGTT-3′ (SEQ ID NO: 152)5′-UUACAGUUGUUGGGGUUGGUGCUGUUG-3′ (SEQ ID NO: 369)3′-AAUGUCAACAACCCCAACCACGACAAC-5′ (SEQ ID NO: 81) LDHA-366 Target:5′-TTACAGTTGTTGGGGTTGGTGCTGTTG-3′ (SEQ ID NO: 153)5′-UACAGUUGUUGGGGUUGGUGCUGUUGG-3′ (SEQ ID NO: 370)3′-AUGUCAACAACCCCAACCACGACAACC-5′ (SEQ ID NO: 82) LDHA-367 Target:5′-TACAGTTGTTGGGGTTGGTGCTGTTGG-3′ (SEQ ID NO: 154)5′-CAGUUGUUGGGGUUGGUGCUGUUGGCA-3′ (SEQ ID NO: 371)3′-GUCAACAACCCCAACCACGACAACCGU-5′ (SEQ ID NO: 83) LDHA-369 Target:5′-CAGTTGTTGGGGTTGGTGCTGTTGGCA-3′ (SEQ ID NO: 155)5′-AGUUGUUGGGGUUGGUGCUGUUGGCAU-3′ (SEQ ID NO: 372)3′-UCAACAACCCCAACCACGACAACCGUA-5′ (SEQ ID NO: 84) LDHA-370 Target:5′-AGTTGTTGGGGTTGGTGCTGTTGGCAT-3′ (SEQ ID NO: 156)5′-GGCCUGUGCCAUCAGUAUCUUAAUGAA-3′ (SEQ ID NO: 373)3′-CCGGACACGGUAGUCAUAGAAUUACUU-5′ (SEQ ID NO: 85) LDHA-397 Target:5′-GGCCTGTGCCATCAGTATCTTAATGAA-3′ (SEQ ID NO: 157)5′-GCCUGUGCCAUCAGUAUCUUAAUGAAG-3′ (SEQ ID NO: 374)3′-CGGACACGGUAGUCAUAGAAUUACUUC-5′ (SEQ ID NO: 86) LDHA-398 Target:5′-GCCTGTGCCATCAGTATCTTAATGAAG-3′ (SEQ ID NO: 158)5′-CCUGUGCCAUCAGUAUCUUAAUGAAGG-3′ (SEQ ID NO: 375)3′-GGACACGGUAGUCAUAGAAUUACUUCC-5′ (SEQ ID NO: 87) LDHA-399 Target:5′-CCTGTGCCATCAGTATCTTAATGAAGG-3′ (SEQ ID NO: 159)5′-CUGUGCCAUCAGUAUCUUAAUGAAGGA-3′ (SEQ ID NO: 376)3′-GACACGGUAGUCAUAGAAUUACUUCCU-5′ (SEQ ID NO: 88) LDHA-400 Target:5′-CTGTGCCATCAGTATCTTAATGAAGGA-3′ (SEQ ID NO: 160)5′-UGUGCCAUCAGUAUCUUAAUGAAGGAC-3′ (SEQ ID NO: 377)3′-ACACGGUAGUCAUAGAAUUACUUCCUG-5′ (SEQ ID NO: 89) LDHA-401 Target:5′-TGTGCCATCAGTATCTTAATGAAGGAC-3′ (SEQ ID NO: 161)5′-GUGCCAUCAGUAUCUUAAUGAAGGACU-3′ (SEQ ID NO: 378)3′-CACGGUAGUCAUAGAAUUACUUCCUGA-5′ (SEQ ID NO: 90) LDHA-402 Target:5′-GTGCCATCAGTATCTTAATGAAGGACT-3′ (SEQ ID NO: 162)5′-UGCCAUCAGUAUCUUAAUGAAGGACUU-3′ (SEQ ID NO: 379)3′-ACGGUAGUCAUAGAAUUACUUCCUGAA-5′ (SEQ ID NO: 91) LDHA-403 Target:5′-TGCCATCAGTATCTTAATGAAGGACTT-3′ (SEQ ID NO: 163)5′-GCCAUCAGUAUCUUAAUGAAGGACUUG-3′ (SEQ ID NO: 380)3′-CGGUAGUCAUAGAAUUACUUCCUGAAC-5′ (SEQ ID NO: 92) LDHA-404 Target:5′-GCCATCAGTATCTTAATGAAGGACTTG-3′ (SEQ ID NO: 164)5′-CAGUGGAUAUCUUGACCUACGUGGCUU-3′ (SEQ ID NO: 381)3′-GUCACCUAUAGAACUGGAUGCACCGAA-5′ (SEQ ID NO: 93) LDHA-714 Target:5′-CAGTGGATATCTTGACCTACGTGGCTT-3′ (SEQ ID NO: 165)5′-UGGAUAUCUUGACCUACGUGGCUUGGA-3′ (SEQ ID NO: 382)3′-ACCUAUAGAACUGGAUGCACCGAACCU-5′ (SEQ ID NO: 94) LDHA-717 Target:5′-TGGATATCTTGACCTACGTGGCTTGGA-3′ (SEQ ID NO: 166)5′-GGAUAUCUUGACCUACGUGGCUUGGAA-3′ (SEQ ID NO: 383)3′-CCUAUAGAACUGGAUGCACCGAACCUU-5′ (SEQ ID NO: 95) LDHA-718 Target:5′-GGATATCTTGACCTACGTGGCTTGGAA-3′ (SEQ ID NO: 167)5′-GAUAUCUUGACCUACGUGGCUUGGAAG-3′ (SEQ ID NO: 384)3′-CUAUAGAACUGGAUGCACCGAACCUUC-5′ (SEQ ID NO: 96) LDHA-719 Target:5′-GATATCTTGACCTACGTGGCTTGGAAG-3′ (SEQ ID NO: 168)5′-AUAUCUUGACCUACGUGGCUUGGAAGA-3′ (SEQ ID NO: 385)3′-UAUAGAACUGGAUGCACCGAACCUUCU-5′ (SEQ ID NO: 97) LDHA-720 Target:5′-ATATCTTGACCTACGTGGCTTGGAAGA-3′ (SEQ ID NO: 169)5′-AUCUUGACCUACGUGGCUUGGAAGAUA-3′ (SEQ ID NO: 386)3′-UAGAACUGGAUGCACCGAACCUUCUAU-5′ (SEQ ID NO: 98) LDHA-722 Target:5′-ATCTTGACCTACGTGGCTTGGAAGATA-3′ (SEQ ID NO: 170)5′-UCUUGACCUACGUGGCUUGGAAGAUAA-3′ (SEQ ID NO: 387)3′-AGAACUGGAUGCACCGAACCUUCUAUU-5′ (SEQ ID NO: 99) LDHA-723 Target:5′-TCTTGACCTACGTGGCTTGGAAGATAA-3′ (SEQ ID NO: 171)5′-CUUGACCUACGUGGCUUGGAAGAUAAG-3′ (SEQ ID NO: 388)3′-GAACUGGAUGCACCGAACCUUCUAUUC-5′ (SEQ ID NO: 100) LDHA-724 Target:5′-CTTGACCTACGTGGCTTGGAAGATAAG-3′ (SEQ ID NO: 172)5′-UUGGAAGAUAAGUGGUUUUCCCAAAAA-3′ (SEQ ID NO: 389)3′-AACCUUCUAUUCACCAAAAGGGUUUUU-5′ (SEQ ID NO: 101) LDHA-739 Target:5′-TTGGAAGATAAGTGGTTTTCCCAAAAA-3′ (SEQ ID NO: 173)5′-UGGAAGAUAAGUGGUUUUCCCAAAAAC-3′ (SEQ ID NO: 390)3′-ACCUUCUAUUCACCAAAAGGGUUUUUG-5′ (SEQ ID NO: 102) LDHA-740 Target:5′-TGGAAGATAAGTGGTTTTCCCAAAAAC-3′ (SEQ ID NO: 174)5′-UGCCUGUAUGGAGUGGAAUGAAUGUUG-3′ (SEQ ID NO: 391)3′-ACGGACAUACCUCACCUUACUUACAAC-5′ (SEQ ID NO: 103) LDHA-891 Target:5′-TGCCTGTATGGAGTGGAATGAATGTTG-3′ (SEQ ID NO: 175)5′-GCCUGUAUGGAGUGGAAUGAAUGUUGC-3′ (SEQ ID NO: 392)3′-CGGACAUACCUCACCUUACUUACAACG-5′ (SEQ ID NO: 104) LDHA-892 Target:5′-GCCTGTATGGAGTGGAATGAATGTTGC-3′ (SEQ ID NO: 176)5′-AAUGAAUGUUGCUGGUGUCUCUCUGAA-3′ (SEQ ID NO: 393)3′-UUACUUACAACGACCACAGAGAGACUU-5′ (SEQ ID NO: 105) LDHA-907 Target:5′-AATGAATGTTGCTGGTGTCTCTCTGAA-3′ (SEQ ID NO: 177)5′-AGGGACUGAUAAAGAUAAGGAACAGUG-3′ (SEQ ID NO: 394)3′-UCCCUGACUAUUUCUAUUCCUUGUCAC-5′ (SEQ ID NO: 106) LDHA-952 Target:5′-AGGGACTGATAAAGATAAGGAACAGTG-3′ (SEQ ID NO: 178)5′-CUGCAAUUUUAAAGUCUUCUGAUGUCA-3′ (SEQ ID NO: 395)3′-GACGUUAAAAUUUCAGAAGACUACAGU-5′ (SEQ ID NO: 107) LDHA-1286 Target:5′-CTGCAATTTTAAAGTCTTCTGATGTCA-3′ (SEQ ID NO: 179)5′-UGCAAUUUUAAAGUCUUCUGAUGUCAU-3′ (SEQ ID NO: 396)3′-ACGUUAAAAUUUCAGAAGACUACAGUA-5′ (SEQ ID NO: 108) LDHA-1287 Target:5′-TGCAATTTTAAAGTCTTCTGATGTCAT-3′ (SEQ ID NO: 180)5′-UUUUAAAGUCUUCUGAUGUCAUAUCAU-3′ (SEQ ID NO: 397)3′-AAAAUUUCAGAAGACUACAGUAUAGUA-5′ (SEQ ID NO: 109) LDHA-1292 Target:5′-TTTTAAAGTCTTCTGATGTCATATCAT-3′ (SEQ ID NO: 181)5′-UUUAAAGUCUUCUGAUGUCAUAUCAUU-3′ (SEQ ID NO: 398)3′-AAAUUUCAGAAGACUACAGUAUAGUAA-5′ (SEQ ID NO: 110) LDHA-1293 Target:5′-TTTAAAGTCTTCTGATGTCATATCATT-3′ (SEQ ID NO: 182)5′-UUAAAGUCUUCUGAUGUCAUAUCAUUU-3′ (SEQ ID NO: 399)3′-AAUUUCAGAAGACUACAGUAUAGUAAA-5′ (SEQ ID NO: 111) LDHA-1294 Target:5′-TTAAAGTCTTCTGATGTCATATCATTT-3′ (SEQ ID NO: 183)5′-UGCAUGUUGUCCUUUUUAUCUGAUCUG-3′ (SEQ ID NO: 400)3′-ACGUACAACAGGAAAAAUAGACUAGAC-5′ (SEQ ID NO: 112) LDHA-1359 Target:5′-TGCATGTTGTCCTTTTTATCTGATCTG-3′ (SEQ ID NO: 184)5′-GCAUGUUGUCCUUUUUAUCUGAUCUGU-3′ (SEQ ID NO: 401)3′-CGUACAACAGGAAAAAUAGACUAGACA-5′ (SEQ ID NO: 113) LDHA-1360 Target:5′-GCATGTTGTCCTTTTTATCTGATCTGT-3′ (SEQ ID NO: 185)5′-CAUGUUGUCCUUUUUAUCUGAUCUGUG-3′ (SEQ ID NO: 402)3′-GUACAACAGGAAAAAUAGACUAGACAC-5′ (SEQ ID NO: 114) LDHA-1361 Target:5′-CATGTTGTCCTTTTTATCTGATCTGTG-3′ (SEQ ID NO: 186)5′-AUGUUGUCCUUUUUAUCUGAUCUGUGA-3′ (SEQ ID NO: 403)3′-UACAACAGGAAAAAUAGACUAGACACU-5′ (SEQ ID NO: 115) LDHA-1362 Target:5′-ATGTTGTCCTTTTTATCTGATCTGTGA-3′ (SEQ ID NO: 187)5′-UGUUGUCCUUUUUAUCUGAUCUGUGAU-3′ (SEQ ID NO: 404)3′-ACAACAGGAAAAAUAGACUAGACACUA-5′ (SEQ ID NO: 116) LDHA-1363 Target:5′-TGTTGTCCTTTTTATCTGATCTGTGAT-3′ (SEQ ID NO: 188)5′-UUGUCCUUUUUAUCUGAUCUGUGAUUA-3′ (SEQ ID NO: 405)3′-AACAGGAAAAAUAGACUAGACACUAAU-5′ (SEQ ID NO: 117) LDHA-1365 Target:5′-TTGTCCTTTTTATCTGATCTGTGATTA-3′ (SEQ ID NO: 189)5′-UGUCCUUUUUAUCUGAUCUGUGAUUAA-3′ (SEQ ID NO: 406)3′-ACAGGAAAAAUAGACUAGACACUAAUU-5′ (SEQ ID NO: 118) LDHA-1366 Target:5′-TGTCCTTTTTATCTGATCTGTGATTAA-3′ (SEQ ID NO: 190)5′-GUCCUUUUUAUCUGAUCUGUGAUUAAA-3′ (SEQ ID NO: 407)3′-CAGGAAAAAUAGACUAGACACUAAUUU-5′ (SEQ ID NO: 119) LDHA-1367 Target:5′-GTCCTTTTTATCTGATCTGTGATTAAA-3′ (SEQ ID NO: 191)5′-UCCUUUUUAUCUGAUCUGUGAUUAAAG-3′ (SEQ ID NO: 408)3′-AGGAAAAAUAGACUAGACACUAAUUUC-5′ (SEQ ID NO: 120) LDHA-1368 Target:5′-TCCTTTTTATCTGATCTGTGATTAAAG-3′ (SEQ ID NO: 192)5′-CUUUUUAUCUGAUCUGUGAUUAAAGCA-3′ (SEQ ID NO: 409)3′-GAAAAAUAGACUAGACACUAAUUUCGU-5′ (SEQ ID NO: 121) LDHA-1370 Target:5′-CTTTTTATCTGATCTGTGATTAAAGCA-3′ (SEQ ID NO: 193)5′-UUUUUAUCUGAUCUGUGAUUAAAGCAG-3′ (SEQ ID NO: 410)3′-AAAAAUAGACUAGACACUAAUUUCGUC-5′ (SEQ ID NO: 122) LDHA-1371 Target:5′-TTTTTATCTGATCTGTGATTAAAGCAG-3′ (SEQ ID NO: 194)5′-UUUUAUCUGAUCUGUGAUUAAAGCAGU-3′ (SEQ ID NO: 411)3′-AAAAUAGACUAGACACUAAUUUCGUCA-5′ (SEQ ID NO: 123) LDHA-1372 Target:5′-TTTTATCTGATCTGTGATTAAAGCAGT-3′ (SEQ ID NO: 195)5′-AGCAGUAAUAUUUUAAGAUGGACUGGG-3′ (SEQ ID NO: 412)3′-UCGUCAUUAUAAAAUUCUACCUGACCC-5′ (SEQ ID NO: 124) LDHA-1393 Target:5′-AGCAGTAATATTTTAAGATGGACTGGG-3′ (SEQ ID NO: 196)5′-UCAACUCCUGAAGUUAGAAAUAAGAAU-3′ (SEQ ID NO: 413)3′-AGUUGAGGACUUCAAUCUUUAUUCUUA-5′ (SEQ ID NO: 125) LDHA-1427 Target:5′-TCAACTCCTGAAGTTAGAAATAAGAAT-3′ (SEQ ID NO: 197)5′-CAACUCCUGAAGUUAGAAAUAAGAAUG-3′ (SEQ ID NO: 414)3′-GUUGAGGACUUCAAUCUUUAUUCUUAC-5′ (SEQ ID NO: 126) LDHA-1428 Target:5′-CAACTCCTGAAGTTAGAAATAAGAATG-3′ (SEQ ID NO: 198)5′-UCAACUGGUUAGUGUGAAAUAGUUCUG-3′ (SEQ ID NO: 415)3′-AGUUGACCAAUCACACUUUAUCAAGAC-5′ (SEQ ID NO: 127) LDHA-1512 Target:5′-TCAACTGGTTAGTGTGAAATAGTTCTG-3′ (SEQ ID NO: 199)5′-CAACUGGUUAGUGUGAAAUAGUUCUGC-3′ (SEQ ID NO: 416)3′-GUUGACCAAUCACACUUUAUCAAGACG-5′ (SEQ ID NO: 128) LDHA-1513 Target:5′-CAACTGGTTAGTGTGAAATAGTTCTGC-3′ (SEQ ID NO: 200)5′-AACUGGUUAGUGUGAAAUAGUUCUGCC-3′ (SEQ ID NO: 417)3′-UUGACCAAUCACACUUUAUCAAGACGG-5′ (SEQ ID NO: 129) LDHA-1514 Target:5′-AACTGGTTAGTGTGAAATAGTTCTGCC-3′ (SEQ ID NO: 201)5′-CUGGUUAGUGUGAAAUAGUUCUGCCAC-3′ (SEQ ID NO: 418)3′-GACCAAUCACACUUUAUCAAGACGGUG-5′ (SEQ ID NO: 130) LDHA-1516 Target:5′-CTGGTTAGTGTGAAATAGTTCTGCCAC-3′ (SEQ ID NO: 202)5′-GGAUCCAGUGUAUAAAUCCAAUAUCAU-3′ (SEQ ID NO: 419)3′-CCUAGGUCACAUAUUUAGGUUAUAGUA-5′ (SEQ ID NO: 131) LDHA-1684 Target:5′-GGATCCAGTGTATAAATCCAATATCAT-3′ (SEQ ID NO: 203)5′-CCAGUGUAUAAAUCCAAUAUCAUGUCU-3′ (SEQ ID NO: 420)3′-GGUCACAUAUUUAGGUUAUAGUACAGA-5′ (SEQ ID NO: 132) LDHA-1688 Target:5′-CCAGTGTATAAATCCAATATCATGTCT-3′ (SEQ ID NO: 204)5′-AUCUUAUUUUGUGAACUAUAUCAGUAG-3′ (SEQ ID NO: 421)3′-UAGAAUAAAACACUUGAUAUAGUCAUC-5′ (SEQ ID NO: 133) LDHA-1736 Target:5′-ATCTTATTTTGTGAACTATATCAGTAG-3′ (SEQ ID NO: 205)5′-ACUAUAUCAGUAGUGUACAUUACCAUA-3′ (SEQ ID NO: 422)3′-UGAUAUAGUCAUCACAUGUAAUGGUAU-5′ (SEQ ID NO: 134) LDHA-1750 Target:5′-ACTATATCAGTAGTGTACATTACCATA-3′ (SEQ ID NO: 206)5′-AUAUCAGUAGUGUACAUUACCAUAUAA-3′ (SEQ ID NO: 423)3′-UAUAGUCAUCACAUGUAAUGGUAUAUU-5′ (SEQ ID NO: 135) LDHA-1753 Target:5′-ATATCAGTAGTGTACATTACCATATAA-3′ (SEQ ID NO: 207)5′-UAUCAGUAGUGUACAUUACCAUAUAAU-3′ (SEQ ID NO: 424)3′-AUAGUCAUCACAUGUAAUGGUAUAUUA-5′ (SEQ ID NO: 136) LDHA-1754 Target:5′-TATCAGTAGTGTACATTACCATATAAT-3′ (SEQ ID NO: 208)5′-UGCAACCAACUAUCCAAGUGUUAUACC-3′ (SEQ ID NO: 425)3′-ACGUUGGUUGAUAGGUUCACAAUAUGG-5′ (SEQ ID NO: 137) LDHA-1805 Target:5′-TGCAACCAACTATCCAAGTGTTATACC-3′ (SEQ ID NO: 209)5′-GCAACCAACUAUCCAAGUGUUAUACCA-3′ (SEQ ID NO: 426)3′-CGUUGGUUGAUAGGUUCACAAUAUGGU-5′ (SEQ ID NO: 138) LDHA-1806 Target:5′-GCAACCAACTATCCAAGTGTTATACCA-3′ (SEQ ID NO: 210)5′-CAACCAACUAUCCAAGUGUUAUACCAA-3′ (SEQ ID NO: 427)3′-GUUGGUUGAUAGGUUCACAAUAUGGUU-5′ (SEQ ID NO: 139) LDHA-1807 Target:5′-CAACCAACTATCCAAGTGTTATACCAA-3′ (SEQ ID NO: 211)5′-AACCAACUAUCCAAGUGUUAUACCAAC-3′ (SEQ ID NO: 428)3′-UUGGUUGAUAGGUUCACAAUAUGGUUG-5′ (SEQ ID NO: 140) LDHA-1808 Target:5′-AACCAACTATCCAAGTGTTATACCAAC-3′ (SEQ ID NO: 212)5′-CAACUAUCCAAGUGUUAUACCAACUAA-3′ (SEQ ID NO: 429)3′-GUUGAUAGGUUCACAAUAUGGUUGAUU-5′ (SEQ ID NO: 141) LDHA-1811 Target:5′-CAACTATCCAAGTGTTATACCAACTAA-3′ (SEQ ID NO: 213)5′-AACUAUCCAAGUGUUAUACCAACUAAA-3′ (SEQ ID NO: 430)3′-UUGAUAGGUUCACAAUAUGGUUGAUUU-5′ (SEQ ID NO: 142) LDHA-1812 Target:5′-AACTATCCAAGTGTTATACCAACTAAA-3′ (SEQ ID NO: 214)5′-UAUCCAAGUGUUAUACCAACUAAAACC-3′ (SEQ ID NO: 431)3′-AUAGGUUCACAAUAUGGUUGAUUUUGG-5′ (SEQ ID NO: 143) LDHA-1815 Target:5′-TATCCAAGTGTTATACCAACTAAAACC-3′ (SEQ ID NO: 215)5′-AUCCAAGUGUUAUACCAACUAAAACCC-3′ (SEQ ID NO: 432)3′-UAGGUUCACAAUAUGGUUGAUUUUGGG-5′ (SEQ ID NO: 144) LDHA-1816 Target:5′-ATCCAAGTGTTATACCAACTAAAACCC-3′ (SEQ ID NO: 216)

TABLE 6 DsiRNA Component 19 Nucleotide Target Sequences in Human LactateDehydrogenase mRNA LDHA-355 19 nt Target #1: 5′-AGAAUAAGAUUACAGUUGU-3′(SEQ ID NO: 433) LDHA-355 19 nt Target #2: 5′-CAGAAUAAGAUUACAGUUG-3′(SEQ ID NO: 505) LDHA-355 19 nt Target #3: 5′-CCAGAAUAAGAUUACAGUU-3′(SEQ ID NO: 577) LDHA-356 19 nt Target #1: 5′-GAAUAAGAUUACAGUUGUU-3′(SEQ ID NO: 434) LDHA-356 19 nt Target #2: 5′-AGAAUAAGAUUACAGUUGU-3′(SEQ ID NO: 506) LDHA-356 19 nt Target #3: 5′-CAGAAUAAGAUUACAGUUG-3′(SEQ ID NO: 578) LDHA-360 19 nt Target #1: 5′-AAGAUUACAGUUGUUGGGG-3′(SEQ ID NO: 435) LDHA-360 19 nt Target #2: 5′-UAAGAUUACAGUUGUUGGG-3′(SEQ ID NO: 507) LDHA-360 19 nt Target #3: 5′-AUAAGAUUACAGUUGUUGG-3′(SEQ ID NO: 579) LDHA-361 19 nt Target #1: 5′-AGAUUACAGUUGUUGGGGU-3′(SEQ ID NO: 436) LDHA-361 19 nt Target #2: 5′-AAGAUUACAGUUGUUGGGG-3′(SEQ ID NO: 508) LDHA-361 19 nt Target #3: 5′-UAAGAUUACAGUUGUUGGG-3′(SEQ ID NO: 580) LDHA-362 19 nt Target #1: 5′-GAUUACAGUUGUUGGGGUU-3′(SEQ ID NO: 437) LDHA-362 19 nt Target #2: 5′-AGAUUACAGUUGUUGGGGU-3′(SEQ ID NO: 509) LDHA-362 19 nt Target #3: 5′-AAGAUUACAGUUGUUGGGG-3′(SEQ ID NO: 581) LDHA-363 19 nt Target #1: 5′-AUUACAGUUGUUGGGGUUG-3′(SEQ ID NO: 438) LDHA-363 19 nt Target #2: 5′-GAUUACAGUUGUUGGGGUU-3′(SEQ ID NO: 510) LDHA-363 19 nt Target #3: 5′-AGAUUACAGUUGUUGGGGU-3′(SEQ ID NO: 582) LDHA-364 19 nt Target #1: 5′-UUACAGUUGUUGGGGUUGG-3′(SEQ ID NO: 439) LDHA-364 19 nt Target #2: 5′-AUUACAGUUGUUGGGGUUG-3′(SEQ ID NO: 511) LDHA-364 19 nt Target #3: 5′-GAUUACAGUUGUUGGGGUU-3′(SEQ ID NO: 583) LDHA-365 19 nt Target #1: 5′-UACAGUUGUUGGGGUUGGU-3′(SEQ ID NO: 440) LDHA-365 19 nt Target #2: 5′-UUACAGUUGUUGGGGUUGG-3′(SEQ ID NO: 512) LDHA-365 19 nt Target #3: 5′-AUUACAGUUGUUGGGGUUG-3′(SEQ ID NO: 584) LDHA-366 19 nt Target #1: 5′-ACAGUUGUUGGGGUUGGUG-3′(SEQ ID NO: 441) LDHA-366 19 nt Target #2: 5′-UACAGUUGUUGGGGUUGGU-3′(SEQ ID NO: 513) LDHA-366 19 nt Target #3: 5′-UUACAGUUGUUGGGGUUGG-3′(SEQ ID NO: 585) LDHA-367 19 nt Target #1: 5′-CAGUUGUUGGGGUUGGUGC-3′(SEQ ID NO: 442) LDHA-367 19 nt Target #2: 5′-ACAGUUGUUGGGGUUGGUG-3′(SEQ ID NO: 514) LDHA-367 19 nt Target #3: 5′-UACAGUUGUUGGGGUUGGU-3′(SEQ ID NO: 586) LDHA-369 19 nt Target #1: 5′-GUUGUUGGGGUUGGUGCUG-3′(SEQ ID NO: 443) LDHA-369 19 nt Target #2: 5′-AGUUGUUGGGGUUGGUGCU-3′(SEQ ID NO: 515) LDHA-369 19 nt Target #3: 5′-CAGUUGUUGGGGUUGGUGC-3′(SEQ ID NO: 587) LDHA-370 19 nt Target #1: 5′-UUGUUGGGGUUGGUGCUGU-3′(SEQ ID NO: 444) LDHA-370 19 nt Target #2: 5′-GUUGUUGGGGUUGGUGCUG-3′(SEQ ID NO: 516) LDHA-370 19 nt Target #3: 5′-AGUUGUUGGGGUUGGUGCU-3′(SEQ ID NO: 588) LDHA-397 19 nt Target #1: 5′-CCUGUGCCAUCAGUAUCUU-3′(SEQ ID NO: 445) LDHA-397 19 nt Target #2: 5′-GCCUGUGCCAUCAGUAUCU-3′(SEQ ID NO: 517) LDHA-397 19 nt Target #3: 5′-GGCCUGUGCCAUCAGUAUC-3′(SEQ ID NO: 589) LDHA-398 19 nt Target #1: 5′-CUGUGCCAUCAGUAUCUUA-3′(SEQ ID NO: 446) LDHA-398 19 nt Target #2: 5′-CCUGUGCCAUCAGUAUCUU-3′(SEQ ID NO: 518) LDHA-398 19 nt Target #3: 5′-GCCUGUGCCAUCAGUAUCU-3′(SEQ ID NO: 590) LDHA-399 19 nt Target #1: 5′-UGUGCCAUCAGUAUCUUAA-3′(SEQ ID NO: 447) LDHA-399 19 nt Target #2: 5′-CUGUGCCAUCAGUAUCUUA-3′(SEQ ID NO: 519) LDHA-399 19 nt Target #3: 5′-CCUGUGCCAUCAGUAUCUU-3′(SEQ ID NO: 591) LDHA-400 19 nt Target #1: 5′-GUGCCAUCAGUAUCUUAAU-3′(SEQ ID NO: 448) LDHA-400 19 nt Target #2: 5′-UGUGCCAUCAGUAUCUUAA-3′(SEQ ID NO: 520) LDHA-400 19 nt Target #3: 5′-CUGUGCCAUCAGUAUCUUA-3′(SEQ ID NO: 592) LDHA-401 19 nt Target #1: 5′-UGCCAUCAGUAUCUUAAUG-3′(SEQ ID NO: 449) LDHA-401 19 nt Target #2: 5′-GUGCCAUCAGUAUCUUAAU-3′(SEQ ID NO: 521) LDHA-401 19 nt Target #3: 5′-UGUGCCAUCAGUAUCUUAA-3′(SEQ ID NO: 593) LDHA-402 19 nt Target #1: 5′-GCCAUCAGUAUCUUAAUGA-3′(SEQ ID NO: 450) LDHA-402 19 nt Target #2: 5′-UGCCAUCAGUAUCUUAAUG-3′(SEQ ID NO: 522) LDHA-402 19 nt Target #3: 5′-GUGCCAUCAGUAUCUUAAU-3′(SEQ ID NO: 594) LDHA-403 19 nt Target #1: 5′-CCAUCAGUAUCUUAAUGAA-3′(SEQ ID NO: 451) LDHA-403 19 nt Target #2: 5′-GCCAUCAGUAUCUUAAUGA-3′(SEQ ID NO: 523) LDHA-403 19 nt Target #3: 5′-UGCCAUCAGUAUCUUAAUG-3′(SEQ ID NO: 595) LDHA-404 19 nt Target #1: 5′-CAUCAGUAUCUUAAUGAAG-3′(SEQ ID NO: 452) LDHA-404 19 nt Target #2: 5′-CCAUCAGUAUCUUAAUGAA-3′(SEQ ID NO: 524) LDHA-404 19 nt Target #3: 5′-GCCAUCAGUAUCUUAAUGA-3′(SEQ ID NO: 596) LDHA-714 19 nt Target #1: 5′-GUGGAUAUCUUGACCUACG-3′(SEQ ID NO: 453) LDHA-714 19 nt Target #2: 5′-AGUGGAUAUCUUGACCUAC-3′(SEQ ID NO: 525) LDHA-714 19 nt Target #3: 5′-CAGUGGAUAUCUUGACCUA-3′(SEQ ID NO: 597) LDHA-717 19 nt Target #1: 5′-GAUAUCUUGACCUACGUGG-3′(SEQ ID NO: 454) LDHA-717 19 nt Target #2: 5′-GGAUAUCUUGACCUACGUG-3′(SEQ ID NO: 526) LDHA-717 19 nt Target #3: 5′-UGGAUAUCUUGACCUACGU-3′(SEQ ID NO: 598) LDHA-718 19 nt Target #1: 5′-AUAUCUUGACCUACGUGGC-3′(SEQ ID NO: 455) LDHA-718 19 nt Target #2: 5′-GAUAUCUUGACCUACGUGG-3′(SEQ ID NO: 527) LDHA-718 19 nt Target #3: 5′-GGAUAUCUUGACCUACGUG-3′(SEQ ID NO: 599) LDHA-719 19 nt Target #1: 5′-UAUCUUGACCUACGUGGCU-3′(SEQ ID NO: 456) LDHA-719 19 nt Target #2: 5′-AUAUCUUGACCUACGUGGC-3′(SEQ ID NO: 528) LDHA-719 19 nt Target #3: 5′-GAUAUCUUGACCUACGUGG-3′(SEQ ID NO: 600) LDHA-720 19 nt Target #1: 5′-AUCUUGACCUACGUGGCUU-3′(SEQ ID NO: 457) LDHA-720 19 nt Target #2: 5′-UAUCUUGACCUACGUGGCU-3′(SEQ ID NO: 529) LDHA-720 19 nt Target #3: 5′-AUAUCUUGACCUACGUGGC-3′(SEQ ID NO: 601) LDHA-722 19 nt Target #1: 5′-CUUGACCUACGUGGCUUGG-3′(SEQ ID NO: 458) LDHA-722 19 nt Target #2: 5′-UCUUGACCUACGUGGCUUG-3′(SEQ ID NO: 530) LDHA-722 19 nt Target #3: 5′-AUCUUGACCUACGUGGCUU-3′(SEQ ID NO: 602) LDHA-723 19 nt Target #1: 5′-UUGACCUACGUGGCUUGGA-3′(SEQ ID NO: 459) LDHA-723 19 nt Target #2: 5′-CUUGACCUACGUGGCUUGG-3′(SEQ ID NO: 531) LDHA-723 19 nt Target #3: 5′-UCUUGACCUACGUGGCUUG-3′(SEQ ID NO: 603) LDHA-724 19 nt Target #1: 5′-UGACCUACGUGGCUUGGAA-3′(SEQ ID NO: 460) LDHA-724 19 nt Target #2: 5′-UUGACCUACGUGGCUUGGA-3′(SEQ ID NO: 532) LDHA-724 19 nt Target #3: 5′-CUUGACCUACGUGGCUUGG-3′(SEQ ID NO: 604) LDHA-739 19 nt Target #1: 5′-GGAAGAUAAGUGGUUUUCC-3′(SEQ ID NO: 461) LDHA-739 19 nt Target #2: 5′-UGGAAGAUAAGUGGUUUUC-3′(SEQ ID NO: 533) LDHA-739 19 nt Target #3: 5′-UUGGAAGAUAAGUGGUUUU-3′(SEQ ID NO: 605) LDHA-740 19 nt Target #1: 5′-GAAGAUAAGUGGUUUUCCC-3′(SEQ ID NO: 462) LDHA-740 19 nt Target #2: 5′-GGAAGAUAAGUGGUUUUCC-3′(SEQ ID NO: 534) LDHA-740 19 nt Target #3: 5′-UGGAAGAUAAGUGGUUUUC-3′(SEQ ID NO: 606) LDHA-891 19 nt Target #1: 5′-CCUGUAUGGAGUGGAAUGA-3′(SEQ ID NO: 463) LDHA-891 19 nt Target #2: 5′-GCCUGUAUGGAGUGGAAUG-3′(SEQ ID NO: 535) LDHA-891 19 nt Target #3: 5′-UGCCUGUAUGGAGUGGAAU-3′(SEQ ID NO: 607) LDHA-892 19 nt Target #1: 5′-CUGUAUGGAGUGGAAUGAA-3′(SEQ ID NO: 464) LDHA-892 19 nt Target #2: 5′-CCUGUAUGGAGUGGAAUGA-3′(SEQ ID NO: 536) LDHA-892 19 nt Target #3: 5′-GCCUGUAUGGAGUGGAAUG-3′(SEQ ID NO: 608) LDHA-907 19 nt Target #1: 5′-UGAAUGUUGCUGGUGUCUC-3′(SEQ ID NO: 465) LDHA-907 19 nt Target #2: 5′-AUGAAUGUUGCUGGUGUCU-3′(SEQ ID NO: 537) LDHA-907 19 nt Target #3: 5′-AAUGAAUGUUGCUGGUGUC-3′(SEQ ID NO: 609) LDHA-952 19 nt Target #1: 5′-GGACUGAUAAAGAUAAGGA-3′(SEQ ID NO: 466) LDHA-952 19 nt Target #2: 5′-GGGACUGAUAAAGAUAAGG-3′(SEQ ID NO: 538) LDHA-952 19 nt Target #3: 5′-AGGGACUGAUAAAGAUAAG-3′(SEQ ID NO: 610) LDHA-1286 19 nt Target #1: 5′-GCAAUUUUAAAGUCUUCUG-3′(SEQ ID NO: 467) LDHA-1286 19 nt Target #2: 5′-UGCAAUUUUAAAGUCUUCU-3′(SEQ ID NO: 539) LDHA-1286 19 nt Target #3: 5′-CUGCAAUUUUAAAGUCUUC-3′(SEQ ID NO: 611) LDHA-1287 19 nt Target #1: 5′-CAAUUUUAAAGUCUUCUGA-3′(SEQ ID NO: 468) LDHA-1287 19 nt Target #2: 5′-GCAAUUUUAAAGUCUUCUG-3′(SEQ ID NO: 540) LDHA-1287 19 nt Target #3: 5′-UGCAAUUUUAAAGUCUUCU-3′(SEQ ID NO: 612) LDHA-1292 19 nt Target #1: 5′-UUAAAGUCUUCUGAUGUCA-3′(SEQ ID NO: 469) LDHA-1292 19 nt Target #2: 5′-UUUAAAGUCUUCUGAUGUC-3′(SEQ ID NO: 541) LDHA-1292 19 nt Target #3: 5′-UUUUAAAGUCUUCUGAUGU-3′(SEQ ID NO: 613) LDHA-1293 19 nt Target #1: 5′-UAAAGUCUUCUGAUGUCAU-3′(SEQ ID NO: 470) LDHA-1293 19 nt Target #2: 5′-UUAAAGUCUUCUGAUGUCA-3′(SEQ ID NO: 542) LDHA-1293 19 nt Target #3: 5′-UUUAAAGUCUUCUGAUGUC-3′(SEQ ID NO: 614) LDHA-1294 19 nt Target #1: 5′-AAAGUCUUCUGAUGUCAUA-3′(SEQ ID NO: 471) LDHA-1294 19 nt Target #2: 5′-UAAAGUCUUCUGAUGUCAU-3′(SEQ ID NO: 543) LDHA-1294 19 nt Target #3: 5′-UUAAAGUCUUCUGAUGUCA-3′(SEQ ID NO: 615) LDHA-1359 19 nt Target #1: 5′-CAUGUUGUCCUUUUUAUCU-3′(SEQ ID NO: 472) LDHA-1359 19 nt Target #2: 5′-GCAUGUUGUCCUUUUUAUC-3′(SEQ ID NO: 544) LDHA-1359 19 nt Target #3: 5′-UGCAUGUUGUCCUUUUUAU-3′(SEQ ID NO: 616) LDHA-1360 19 nt Target #1: 5′-AUGUUGUCCUUUUUAUCUG-3′(SEQ ID NO: 473) LDHA-1360 19 nt Target #2: 5′-CAUGUUGUCCUUUUUAUCU-3′(SEQ ID NO: 545) LDHA-1360 19 nt Target #3: 5′-GCAUGUUGUCCUUUUUAUC-3′(SEQ ID NO: 617) LDHA-1361 19 nt Target #1: 5′-UGUUGUCCUUUUUAUCUGA-3′(SEQ ID NO: 474) LDHA-1361 19 nt Target #2: 5′-AUGUUGUCCUUUUUAUCUG-3′(SEQ ID NO: 546) LDHA-1361 19 nt Target #3: 5′-CAUGUUGUCCUUUUUAUCU-3′(SEQ ID NO: 618) LDHA-1362 19 nt Target #1: 5′-GUUGUCCUUUUUAUCUGAU-3′(SEQ ID NO: 475) LDHA-1362 19 nt Target #2: 5′-UGUUGUCCUUUUUAUCUGA-3′(SEQ ID NO: 547) LDHA-1362 19 nt Target #3: 5′-AUGUUGUCCUUUUUAUCUG-3′(SEQ ID NO: 619) LDHA-1363 19 nt Target #1: 5′-UUGUCCUUUUUAUCUGAUC-3′(SEQ ID NO: 476) LDHA-1363 19 nt Target #2: 5′-GUUGUCCUUUUUAUCUGAU-3′(SEQ ID NO: 548) LDHA-1363 19 nt Target #3: 5′-UGUUGUCCUUUUUAUCUGA-3′(SEQ ID NO: 620) LDHA-1365 19 nt Target #1: 5′-GUCCUUUUUAUCUGAUCUG-3′(SEQ ID NO: 477) LDHA-1365 19 nt Target #2: 5′-UGUCCUUUUUAUCUGAUCU-3′(SEQ ID NO: 549) LDHA-1365 19 nt Target #3: 5′-UUGUCCUUUUUAUCUGAUC-3′(SEQ ID NO: 621) LDHA-1366 19 nt Target #1: 5′-UCCUUUUUAUCUGAUCUGU-3′(SEQ ID NO: 478) LDHA-1366 19 nt Target #2: 5′-GUCCUUUUUAUCUGAUCUG-3′(SEQ ID NO: 550) LDHA-1366 19 nt Target #3: 5′-UGUCCUUUUUAUCUGAUCU-3′(SEQ ID NO: 622) LDHA-1367 19 nt Target #1: 5′-CCUUUUUAUCUGAUCUGUG-3′(SEQ ID NO: 479) LDHA-1367 19 nt Target #2: 5′-UCCUUUUUAUCUGAUCUGU-3′(SEQ ID NO: 551) LDHA-1367 19 nt Target #3: 5′-GUCCUUUUUAUCUGAUCUG-3′(SEQ ID NO: 623) LDHA-1368 19 nt Target #1: 5′-CUUUUUAUCUGAUCUGUGA-3′(SEQ ID NO: 480) LDHA-1368 19 nt Target #2: 5′-CCUUUUUAUCUGAUCUGUG-3′(SEQ ID NO: 552) LDHA-1368 19 nt Target #3: 5′-UCCUUUUUAUCUGAUCUGU-3′(SEQ ID NO: 624) LDHA-1370 19 nt Target #1: 5′-UUUUAUCUGAUCUGUGAUU-3′(SEQ ID NO: 481) LDHA-1370 19 nt Target #2: 5′-UUUUUAUCUGAUCUGUGAU-3′(SEQ ID NO: 553) LDHA-1370 19 nt Target #3: 5′-CUUUUUAUCUGAUCUGUGA-3′(SEQ ID NO: 625) LDHA-1371 19 nt Target #1: 5′-UUUAUCUGAUCUGUGAUUA-3′(SEQ ID NO: 482) LDHA-1371 19 nt Target #2: 5′-UUUUAUCUGAUCUGUGAUU-3′(SEQ ID NO: 554) LDHA-1371 19 nt Target #3: 5′-UUUUUAUCUGAUCUGUGAU-3′(SEQ ID NO: 626) LDHA-1372 19 nt Target #1: 5′-UUAUCUGAUCUGUGAUUAA-3′(SEQ ID NO: 483) LDHA-1372 19 nt Target #2: 5′-UUUAUCUGAUCUGUGAUUA-3′(SEQ ID NO: 555) LDHA-1372 19 nt Target #3: 5′-UUUUAUCUGAUCUGUGAUU-3′(SEQ ID NO: 627) LDHA-1393 19 nt Target #1: 5′-CAGUAAUAUUUUAAGAUGG-3′(SEQ ID NO: 484) LDHA-1393 19 nt Target #2: 5′-GCAGUAAUAUUUUAAGAUG-3′(SEQ ID NO: 556) LDHA-1393 19 nt Target #3: 5′-AGCAGUAAUAUUUUAAGAU-3′(SEQ ID NO: 628) LDHA-1427 19 nt Target #1: 5′-AACUCCUGAAGUUAGAAAU-3′(SEQ ID NO: 485) LDHA-1427 19 nt Target #2: 5′-CAACUCCUGAAGUUAGAAA-3′(SEQ ID NO: 557) LDHA-1427 19 nt Target #3: 5′-UCAACUCCUGAAGUUAGAA-3′(SEQ ID NO: 629) LDHA-1428 19 nt Target #1: 5′-ACUCCUGAAGUUAGAAAUA-3′(SEQ ID NO: 486) LDHA-1428 19 nt Target #2: 5′-AACUCCUGAAGUUAGAAAU-3′(SEQ ID NO: 558) LDHA-1428 19 nt Target #3: 5′-CAACUCCUGAAGUUAGAAA-3′(SEQ ID NO: 630) LDHA-1512 19 nt Target #1: 5′-AACUGGUUAGUGUGAAAUA-3′(SEQ ID NO: 487) LDHA-1512 19 nt Target #2: 5′-CAACUGGUUAGUGUGAAAU-3′(SEQ ID NO: 559) LDHA-1512 19 nt Target #3: 5′-UCAACUGGUUAGUGUGAAA-3′(SEQ ID NO: 631) LDHA-1513 19 nt Target #1: 5′-ACUGGUUAGUGUGAAAUAG-3′(SEQ ID NO: 488) LDHA-1513 19 nt Target #2: 5′-AACUGGUUAGUGUGAAAUA-3′(SEQ ID NO: 560) LDHA-1513 19 nt Target #3: 5′-CAACUGGUUAGUGUGAAAU-3′(SEQ ID NO: 632) LDHA-1514 19 nt Target #1: 5′-CUGGUUAGUGUGAAAUAGU-3′(SEQ ID NO: 489) LDHA-1514 19 nt Target #2: 5′-ACUGGUUAGUGUGAAAUAG-3′(SEQ ID NO: 561) LDHA-1514 19 nt Target #3: 5′-AACUGGUUAGUGUGAAAUA-3′(SEQ ID NO: 633) LDHA-1516 19 nt Target #1: 5′-GGUUAGUGUGAAAUAGUUC-3′(SEQ ID NO: 490) LDHA-1516 19 nt Target #2: 5′-UGGUUAGUGUGAAAUAGUU-3′(SEQ ID NO: 562) LDHA-1516 19 nt Target #3: 5′-CUGGUUAGUGUGAAAUAGU-3′(SEQ ID NO: 634) LDHA-1684 19 nt Target #1: 5′-AUCCAGUGUAUAAAUCCAA-3′(SEQ ID NO: 491) LDHA-1684 19 nt Target #2: 5′-GAUCCAGUGUAUAAAUCCA-3′(SEQ ID NO: 563) LDHA-1684 19 nt Target #3: 5′-GGAUCCAGUGUAUAAAUCC-3′(SEQ ID NO: 635) LDHA-1688 19 nt Target #1: 5′-AGUGUAUAAAUCCAAUAUC-3′(SEQ ID NO: 492) LDHA-1688 19 nt Target #2: 5′-CAGUGUAUAAAUCCAAUAU-3′(SEQ ID NO: 564) LDHA-1688 19 nt Target #3: 5′-CCAGUGUAUAAAUCCAAUA-3′(SEQ ID NO: 636) LDHA-1736 19 nt Target #1: 5′-CUUAUUUUGUGAACUAUAU-3′(SEQ ID NO: 493) LDHA-1736 19 nt Target #2: 5′-UCUUAUUUUGUGAACUAUA-3′(SEQ ID NO: 565) LDHA-1736 19 nt Target #3: 5′-AUCUUAUUUUGUGAACUAU-3′(SEQ ID NO: 637) LDHA-1750 19 nt Target #1: 5′-UAUAUCAGUAGUGUACAUU-3′(SEQ ID NO: 494) LDHA-1750 19 nt Target #2: 5′-CUAUAUCAGUAGUGUACAU-3′(SEQ ID NO: 566) LDHA-1750 19 nt Target #3: 5′-ACUAUAUCAGUAGUGUACA-3′(SEQ ID NO: 638) LDHA-1753 19 nt Target #1: 5′-AUCAGUAGUGUACAUUACC-3′(SEQ ID NO: 495) LDHA-1753 19 nt Target #2: 5′-UAUCAGUAGUGUACAUUAC-3′(SEQ ID NO: 567) LDHA-1753 19 nt Target #3: 5′-AUAUCAGUAGUGUACAUUA-3′(SEQ ID NO: 639) LDHA-1754 19 nt Target #1: 5′-UCAGUAGUGUACAUUACCA-3′(SEQ ID NO: 496) LDHA-1754 19 nt Target #2: 5′-AUCAGUAGUGUACAUUACC-3′(SEQ ID NO: 568) LDHA-1754 19 nt Target #3: 5′-UAUCAGUAGUGUACAUUAC-3′(SEQ ID NO: 640) LDHA-1805 19 nt Target #1: 5′-CAACCAACUAUCCAAGUGU-3′(SEQ ID NO: 497) LDHA-1805 19 nt Target #2: 5′-GCAACCAACUAUCCAAGUG-3′(SEQ ID NO: 569) LDHA-1805 19 nt Target #3: 5′-UGCAACCAACUAUCCAAGU-3′(SEQ ID NO: 641) LDHA-1806 19 nt Target #1: 5′-AACCAACUAUCCAAGUGUU-3′(SEQ ID NO: 498) LDHA-1806 19 nt Target #2: 5′-CAACCAACUAUCCAAGUGU-3′(SEQ ID NO: 570) LDHA-1806 19 nt Target #3: 5′-GCAACCAACUAUCCAAGUG-3′(SEQ ID NO: 642) LDHA-1807 19 nt Target #1: 5′-ACCAACUAUCCAAGUGUUA-3′(SEQ ID NO: 499) LDHA-1807 19 nt Target #2: 5′-AACCAACUAUCCAAGUGUU-3′(SEQ ID NO: 571) LDHA-1807 19 nt Target #3: 5′-CAACCAACUAUCCAAGUGU-3′(SEQ ID NO: 643) LDHA-1808 19 nt Target #1: 5′-CCAACUAUCCAAGUGUUAU-3′(SEQ ID NO: 500) LDHA-1808 19 nt Target #2: 5′-ACCAACUAUCCAAGUGUUA-3′(SEQ ID NO: 572) LDHA-1808 19 nt Target #3: 5′-AACCAACUAUCCAAGUGUU-3′(SEQ ID NO: 644) LDHA-1811 19 nt Target #1: 5′-ACUAUCCAAGUGUUAUACC-3′(SEQ ID NO: 501) LDHA-1811 19 nt Target #2: 5′-AACUAUCCAAGUGUUAUAC-3′(SEQ ID NO: 573) LDHA-1811 19 nt Target #3: 5′-CAACUAUCCAAGUGUUAUA-3′(SEQ ID NO: 645) LDHA-1812 19 nt Target #1: 5′-CUAUCCAAGUGUUAUACCA-3′(SEQ ID NO: 502) LDHA-1812 19 nt Target #2: 5′-ACUAUCCAAGUGUUAUACC-3′(SEQ ID NO: 574) LDHA-1812 19 nt Target #3: 5′-AACUAUCCAAGUGUUAUAC-3′(SEQ ID NO: 646) LDHA-1815 19 nt Target #1: 5′-UCCAAGUGUUAUACCAACU-3′(SEQ ID NO: 503) LDHA-1815 19 nt Target #2: 5′-AUCCAAGUGUUAUACCAAC-3′(SEQ ID NO: 575) LDHA-1815 19 nt Target #3: 5′-UAUCCAAGUGUUAUACCAA-3′(SEQ ID NO: 647) LDHA-1816 19 nt Target #1: 5′-CCAAGUGUUAUACCAACUA-3′(SEQ ID NO: 504) LDHA-1816 19 nt Target #2: 5′-UCCAAGUGUUAUACCAACU-3′(SEQ ID NO: 576) LDHA-1816 19 nt Target #3: 5′-AUCCAAGUGUUAUACCAAC-3′(SEQ ID NO: 648)

TABLE 7 Selected Mouse Anti-Lactate Dehydrogenase DsiRNA Agents(Asymmetrics) 5′-CAAGGACCAGCUGAUUGUGAAUCtt-3′ (SEQ ID NO: 649)3′-GAGUUCCUGGUCGACUAACACUUAGAA-5′ (SEQ ID NO: 697) LDHA-m367 Target:5′-CTCAAGGACCAGCTGATTGTGAATCTT-3′ (SEQ ID NO: 745)5′-AAGGACCAGCUGAUUGUGAAUCUtc-3′ (SEQ ID NO: 650)3′-AGUUCCUGGUCGACUAACACUUAGAAG-5′ (SEQ ID NO: 698) LDHA-m368 Target:5′-TCAAGGACCAGCTGATTGTGAATCTTC-3′ (SEQ ID NO: 746)5′-ACCAGCUGAUUGUGAAUCUUCUUaa-3′ (SEQ ID NO: 651)3′-CCUGGUCGACUAACACUUAGAAGAAUU-5′ (SEQ ID NO: 699) LDHA-m372 Target:5′-GGACCAGCTGATTGTGAATCTTCTTAA-3′ (SEQ ID NO: 747)5′-GCUGAUUGUGAAUCUUCUUAAGGaa-3′ (SEQ ID NO: 652)3′-GUCGACUAACACUUAGAAGAAUUCCUU-5′ (SEQ ID NO: 700) LDHA-m376 Target:5′-CAGCTGATTGTGAATCTTCTTAAGGAA-3′ (SEQ ID NO: 748)5′-CUUGUGCCAUCAGUAUCUUAAUGaa-3′ (SEQ ID NO: 653)3′-CCGAACACGGUAGUCAUAGAAUUACUU-5′ (SEQ ID NO: 701) LDHA-m456 Target:5′-GGCTTGTGCCATCAGTATCTTAATGAA-3′ (SEQ ID NO: 749)5′-CCCUUGUUGACGUCAUGGAAGACaa-3′ (SEQ ID NO: 654)3′-ACGGGAACAACUGCAGUACCUUCUGUU-5′ (SEQ ID NO: 702) LDHA-m501 Target:5′-TGCCCTTGTTGACGTCATGGAAGACAA-3′ (SEQ ID NO: 750)5′-GUUGACGUCAUGGAAGACAAACUca-3′ (SEQ ID NO: 655)3′-AACAACUGCAGUACCUUCUGUUUGAGU-5′ (SEQ ID NO: 703) LDHA-m506 Target:5′-TTGTTGACGTCATGGAAGACAAACTCA-3′ (SEQ ID NO: 751)5′-UUGACGUCAUGGAAGACAAACUCaa-3′ (SEQ ID NO: 656)3′-ACAACUGCAGUACCUUCUGUUUGAGUU-5′ (SEQ ID NO: 704) LDHA-m507 Target:5′-TGTTGACGTCATGGAAGACAAACTCAA-3′ (SEQ ID NO: 752)5′-AUUGUCUCCAGCAAAGACUACUGtg-3′ (SEQ ID NO: 657)3′-UUUAACAGAGGUCGUUUCUGAUGACAC-5′ (SEQ ID NO: 705) LDHA-m584 Target:5′-AAATTGTCTCCAGCAAAGACTACTGTG-3′ (SEQ ID NO: 753)5′-CGAAACGUGAACAUCUUCAAGUUca-3′ (SEQ ID NO: 658)3′-UCGCUUUGCACUUGUAGAAGUUCAAGU-5′ (SEQ ID NO: 706) LDHA-m689 Target:5′-AGCGAAACGTGAACATCTTCAAGTTCA-3′ (SEQ ID NO: 754)5′-CGUGAACAUCUUCAAGUUCAUCAtt-3′ (SEQ ID NO: 659)3′-UUGCACUUGUAGAAGUUCAAGUAGUAA-5′ (SEQ ID NO: 707) LDHA-m694 Target:5′-AACGTGAACATCTTCAAGTTCATCATT-3′ (SEQ ID NO: 755)5′-GUGAACAUCUUCAAGUUCAUCAUtc-3′ (SEQ ID NO: 660)3′-UGCACUUGUAGAAGUUCAAGUAGUAAG-5′ (SEQ ID NO: 708) LDHA-m695 Target:5′-ACGTGAACATCTTCAAGTTCATCATTC-3′ (SEQ ID NO: 756)5′-CCGAGUAAUUGGAAGUGGUUGCAat-3′ (SEQ ID NO: 661)3′-UUGGCUCAUUAACCUUCACCAACGUUA-5′ (SEQ ID NO: 709) LDHA-m823 Target:5′-AACCGAGTAATTGGAAGTGGTTGCAAT-3′ (SEQ ID NO: 757)5′-ACGAGGUGAUCAAGCUGAAAGGUta-3′ (SEQ ID NO: 662)3′-GAUGCUCCACUAGUUCGACUUUCCAAU-5′ (SEQ ID NO: 710) LDHA-m1071 Target:5′-CTACGAGGTGATCAAGCTGAAAGGTTA-3′ (SEQ ID NO: 758)5′-GCUGAGAGCAUAAUGAAGAACCUta-3′ (SEQ ID NO: 663)3′-ACCGACUCUCGUAUUACUUCUUGGAAU-5′ (SEQ ID NO: 711) LDHA-m1133 Target:5′-TGGCTGAGAGCATAATGAAGAACCTTA-3′ (SEQ ID NO: 759)5′-GAUUAAGGGUCUCUAUGGAAUCAat-3′ (SEQ ID NO: 664)3′-UACUAAUUCCCAGAGAUACCUUAGUUA-5′ (SEQ ID NO: 712) LDHA-m1183 Target:5′-ATGATTAAGGGTCTCTATGGAATCAAT-3′ (SEQ ID NO: 760)5′-AAAAUGGAAUCUCGGAUGUUGUGaa-3′ (SEQ ID NO: 665)3′-UGUUUUACCUUAGAGCCUACAACACUU-5′ (SEQ ID NO: 713) LDHA-m1245 Target:5′-ACAAAATGGAATCTCGGATGTTGTGAA-3′ (SEQ ID NO: 761)5′-GGAAUCUCGGAUGUUGUGAAGGUga-3′ (SEQ ID NO: 666)3′-UACCUUAGAGCCUACAACACUUCCACU-5′ (SEQ ID NO: 714) LDHA-m1250 Target:5′-ATGGAATCTCGGATGTTGTGAAGGTGA-3′ (SEQ ID NO: 762)5′-CGGAUGUUGUGAAGGUGACACUGac-3′ (SEQ ID NO: 667)3′-GAGCCUACAACACUUCCACUGUGACUG-5′ (SEQ ID NO: 715) LDHA-m1257 Target:5′-CTCGGATGTTGTGAAGGTGACACTGAC-3′ (SEQ ID NO: 763)5′-GAUGCAUAUCUUGUGCAUAAAUGtt-3′ (SEQ ID NO: 668)3′-UACUACGUAUAGAACACGUAUUUACAA-5′ (SEQ ID NO: 716) LDHA-m1687 Target:5′-ATGATGCATATCTTGTGCATAAATGTT-3′ (SEQ ID NO: 764)5′-AUGCAUAUCUUGUGCAUAAAUGUtg-3′ (SEQ ID NO: 669)3′-ACUACGUAUAGAACACGUAUUUACAAC-5′ (SEQ ID NO: 717) LDHA-m1688 Target:5′-TGATGCATATCTTGTGCATAAATGTTG-3′ (SEQ ID NO: 765)5′-GCAUAUCUUGUGCAUAAAUGUUGta-3′ (SEQ ID NO: 670)3′-UACGUAUAGAACACGUAUUUACAACAU-5′ (SEQ ID NO: 718) LDHA-m1690 Target:5′-ATGCATATCTTGTGCATAAATGTTGTA-3′ (SEQ ID NO: 766)5′-CAUAUCUUGUGCAUAAAUGUUGUac-3′ (SEQ ID NO: 671)3′-ACGUAUAGAACACGUAUUUACAACAUG-5′ (SEQ ID NO: 719) LDHA-m1691 Target:5′-TGCATATCTTGTGCATAAATGTTGTAC-3′ (SEQ ID NO: 767)5′-AUAUCUUGUGCAUAAAUGUUGUAca-3′ (SEQ ID NO: 672)3′-CGUAUAGAACACGUAUUUACAACAUGU-5′ (SEQ ID NO: 720) LDHA-m1692 Target:5′-GCATATCTTGTGCATAAATGTTGTACA-3′ (SEQ ID NO: 768)5′-AUCUUGUGCAUAAAUGUUGUACAgg-3′ (SEQ ID NO: 673)3′-UAUAGAACACGUAUUUACAACAUGUCC-5′ (SEQ ID NO: 721) LDHA-m1694 Target:5′-ATATCTTGTGCATAAATGTTGTACAGG-3′ (SEQ ID NO: 769)5′-UCUUGUGCAUAAAUGUUGUACAGga-3′ (SEQ ID NO: 674)3′-AUAGAACACGUAUUUACAACAUGUCCU-5′ (SEQ ID NO: 722) LDHA-m1695 Target:5′-TATCTTGTGCATAAATGTTGTACAGGA-3′ (SEQ ID NO: 770)5′-UUGUGCAUAAAUGUUGUACAGGAta-3′ (SEQ ID NO: 675)3′-AGAACACGUAUUUACAACAUGUCCUAU-5′ (SEQ ID NO: 723) LDHA-m1697 Target:5′-TCTTGTGCATAAATGTTGTACAGGATA-3′ (SEQ ID NO: 771)5′-UGUGCAUAAAUGUUGUACAGGAUat-3′ (SEQ ID NO: 676)3′-GAACACGUAUUUACAACAUGUCCUAUA-5′ (SEQ ID NO: 724) LDHA-m1698 Target:5′-CTTGTGCATAAATGTTGTACAGGATAT-3′ (SEQ ID NO: 772)5′-GUGCAUAAAUGUUGUACAGGAUAtt-3′ (SEQ ID NO: 677)3′-AACACGUAUUUACAACAUGUCCUAUAA-5′ (SEQ ID NO: 725) LDHA-m1699 Target:5′-TTGTGCATAAATGTTGTACAGGATATT-3′ (SEQ ID NO: 773)5′-UGCAUAAAUGUUGUACAGGAUAUtt-3′ (SEQ ID NO: 678)3′-ACACGUAUUUACAACAUGUCCUAUAAA-5′ (SEQ ID NO: 726) LDHA-m1700 Target:5′-TGTGCATAAATGTTGTACAGGATATTT-3′ (SEQ ID NO: 774)5′-GCAUAAAUGUUGUACAGGAUAUUtt-3′ (SEQ ID NO: 679)3′-CACGUAUUUACAACAUGUCCUAUAAAA-5′ (SEQ ID NO: 727) LDHA-m1701 Target:5′-GTGCATAAATGTTGTACAGGATATTTT-3′ (SEQ ID NO: 775)5′-CAUAAAUGUUGUACAGGAUAUUUta-3′ (SEQ ID NO: 680)3′-ACGUAUUUACAACAUGUCCUAUAAAAU-5′ (SEQ ID NO: 728) LDHA-m1702 Target:5′-TGCATAAATGTTGTACAGGATATTTTA-3′ (SEQ ID NO: 776)5′-AUAAAUGUUGUACAGGAUAUUUUat-3′ (SEQ ID NO: 681)3′-CGUAUUUACAACAUGUCCUAUAAAAUA-5′ (SEQ ID NO: 729) LDHA-m1703 Target:5′-GCATAAATGTTGTACAGGATATTTTAT-3′ (SEQ ID NO: 777)5′-UAAAUGUUGUACAGGAUAUUUUAta-3′ (SEQ ID NO: 682)3′-GUAUUUACAACAUGUCCUAUAAAAUAU-5′ (SEQ ID NO: 730) LDHA-m1704 Target:5′-CATAAATGTTGTACAGGATATTTTATA-3′ (SEQ ID NO: 778)5′-AAAUGUUGUACAGGAUAUUUUAUat-3′ (SEQ ID NO: 683)3′-UAUUUACAACAUGUCCUAUAAAAUAUA-5′ (SEQ ID NO: 731) LDHA-m1705 Target:5′-ATAAATGTTGTACAGGATATTTTATAT-3′ (SEQ ID NO: 779)5′-AAUGUUGUACAGGAUAUUUUAUAta-3′ (SEQ ID NO: 684)3′-AUUUACAACAUGUCCUAUAAAAUAUAU-5′ (SEQ ID NO: 732) LDHA-m1706 Target:5′-TAAATGTTGTACAGGATATTTTATATA-3′ (SEQ ID NO: 780)5′-AUGUUGUACAGGAUAUUUUAUAUat-3′ (SEQ ID NO: 685)3′-UUUACAACAUGUCCUAUAAAAUAUAUA-5′ (SEQ ID NO: 733) LDHA-m1707 Target:5′-AAATGTTGTACAGGATATTTTATATAT-3′ (SEQ ID NO: 781)5′-UGUUGUACAGGAUAUUUUAUAUAtt-3′ (SEQ ID NO: 686)3′-UUACAACAUGUCCUAUAAAAUAUAUAA-5′ (SEQ ID NO: 734) LDHA-m1708 Target:5′-AATGTTGTACAGGATATTTTATATATT-3′ (SEQ ID NO: 782)5′-GUUGUACAGGAUAUUUUAUAUAUta-3′ (SEQ ID NO: 687)3′-UACAACAUGUCCUAUAAAAUAUAUAAU-5′ (SEQ ID NO: 735) LDHA-m1709 Target:5′-ATGTTGTACAGGATATTTTATATATTA-3′ (SEQ ID NO: 783)5′-UUGUACAGGAUAUUUUAUAUAUUat-3′ (SEQ ID NO: 688)3′-ACAACAUGUCCUAUAAAAUAUAUAAUA-5′ (SEQ ID NO: 736) LDHA-m1710 Target:5′-TGTTGTACAGGATATTTTATATATTAT-3′ (SEQ ID NO: 784)5′-GUCUGUAGUGUGCAUUGCAAUAUta-3′ (SEQ ID NO: 689)3′-CACAGACAUCACACGUAACGUUAUAAU-5′ (SEQ ID NO: 737) LDHA-m1739 Target:5′-GTGTCTGTAGTGTGCATTGCAATATTA-3′ (SEQ ID NO: 785)5′-GUAGUGUGCAUUGCAAUAUUAUGtg-3′ (SEQ ID NO: 690)3′-GACAUCACACGUAACGUUAUAAUACAC-5′ (SEQ ID NO: 738) LDHA-m1743 Target:5′-CTGTAGTGTGCATTGCAATATTATGTG-3′ (SEQ ID NO: 786)5′-UAGUGUGCAUUGCAAUAUUAUGUga-3′ (SEQ ID NO: 691)3′-ACAUCACACGUAACGUUAUAAUACACU-5′ (SEQ ID NO: 739) LDHA-m1744 Target:5′-TGTAGTGTGCATTGCAATATTATGTGA-3′ (SEQ ID NO: 787)5′-GUGUGCAUUGCAAUAUUAUGUGAga-3′ (SEQ ID NO: 692)3′-AUCACACGUAACGUUAUAAUACACUCU-5′ (SEQ ID NO: 740) LDHA-m1746 Target:5′-TAGTGTGCATTGCAATATTATGTGAGA-3′ (SEQ ID NO: 788)5′-CAUUGCAAUAUUAUGUGAGAUGUaa-3′ (SEQ ID NO: 693)3′-ACGUAACGUUAUAAUACACUCUACAUU-5′ (SEQ ID NO: 741) LDHA-m1751 Target:5′-TGCATTGCAATATTATGTGAGATGTAA-3′ (SEQ ID NO: 789)5′-AUUGCAAUAUUAUGUGAGAUGUAag-3′ (SEQ ID NO: 694)3′-CGUAACGUUAUAAUACACUCUACAUUC-5′ (SEQ ID NO: 742) LDHA-m1752 Target:5′-GCATTGCAATATTATGTGAGATGTAAG-3′ (SEQ ID NO: 790)5′-GCAAUAUUAUGUGAGAUGUAAGAtc-3′ (SEQ ID NO: 695)3′-AACGUUAUAAUACACUCUACAUUCUAG-5′ (SEQ ID NO: 743) LDHA-m1755 Target:5′-TTGCAATATTATGTGAGATGTAAGATC-3′ (SEQ ID NO: 791)5′-CAAUAUUAUGUGAGAUGUAAGAUct-3′ (SEQ ID NO: 696)3′-ACGUUAUAAUACACUCUACAUUCUAGA-5′ (SEQ ID NO: 744) LDHA-m1756 Target:5′-TGCAATATTATGTGAGATGTAAGATCT-3′ (SEQ ID NO: 792)

TABLE 8 Selected Mouse Anti-Lactate Dehydrogenase DsiRNAs, UnmodifiedDuplexes (Asymmetrics) 5′-CAAGGACCAGCUGAUUGUGAAUCUU-3′ (SEQ ID NO: 793)3′-GAGUUCCUGGUCGACUAACACUUAGAA-5′ (SEQ ID NO: 697) LDHA-m367 Target:5′-CTCAAGGACCAGCTGATTGTGAATCTT-3′ (SEQ ID NO: 745)5′-AAGGACCAGCUGAUUGUGAAUCUUC-3′ (SEQ ID NO: 794)3′-AGUUCCUGGUCGACUAACACUUAGAAG-5′ (SEQ ID NO: 698) LDHA-m368 Target:5′-TCAAGGACCAGCTGATTGTGAATCTTC-3′ (SEQ ID NO: 746)5′-ACCAGCUGAUUGUGAAUCUUCUUAA-3′ (SEQ ID NO: 795)3′-CCUGGUCGACUAACACUUAGAAGAAUU-5′ (SEQ ID NO: 699) LDHA-m372 Target:5′-GGACCAGCTGATTGTGAATCTTCTTAA-3′ (SEQ ID NO: 747)5′-GCUGAUUGUGAAUCUUCUUAAGGAA-3′ (SEQ ID NO: 796)3′-GUCGACUAACACUUAGAAGAAUUCCUU-5′ (SEQ ID NO: 700) LDHA-m376 Target:5′-CAGCTGATTGTGAATCTTCTTAAGGAA-3′ (SEQ ID NO: 748)5′-CUUGUGCCAUCAGUAUCUUAAUGAA-3′ (SEQ ID NO: 797)3′-CCGAACACGGUAGUCAUAGAAUUACUU-5′ (SEQ ID NO: 701) LDHA-m456 Target:5′-GGCTTGTGCCATCAGTATCTTAATGAA-3′ (SEQ ID NO: 749)5′-CCCUUGUUGACGUCAUGGAAGACAA-3′ (SEQ ID NO: 798)3′-ACGGGAACAACUGCAGUACCUUCUGUU-5′ (SEQ ID NO: 702) LDHA-m501 Target:5′-TGCCCTTGTTGACGTCATGGAAGACAA-3′ (SEQ ID NO: 750)5′-GUUGACGUCAUGGAAGACAAACUCA-3′ (SEQ ID NO: 799)3′-AACAACUGCAGUACCUUCUGUUUGAGU-5′ (SEQ ID NO: 703) LDHA-m506 Target:5′-TTGTTGACGTCATGGAAGACAAACTCA-3′ (SEQ ID NO: 751)5′-UUGACGUCAUGGAAGACAAACUCAA-3′ (SEQ ID NO: 800)3′-ACAACUGCAGUACCUUCUGUUUGAGUU-5′ (SEQ ID NO: 704) LDHA-m507 Target:5′-TGTTGACGTCATGGAAGACAAACTCAA-3′ (SEQ ID NO: 752)5′-AUUGUCUCCAGCAAAGACUACUGUG-3′ (SEQ ID NO: 801)3′-UUUAACAGAGGUCGUUUCUGAUGACAC-5′ (SEQ ID NO: 705) LDHA-m584 Target:5′-AAATTGTCTCCAGCAAAGACTACTGTG-3′ (SEQ ID NO: 753)5′-CGAAACGUGAACAUCUUCAAGUUCA-3′ (SEQ ID NO: 802)3′-UCGCUUUGCACUUGUAGAAGUUCAAGU-5′ (SEQ ID NO: 706) LDHA-m689 Target:5′-AGCGAAACGTGAACATCTTCAAGTTCA-3′ (SEQ ID NO: 754)5′-CGUGAACAUCUUCAAGUUCAUCAUU-3′ (SEQ ID NO: 803)3′-UUGCACUUGUAGAAGUUCAAGUAGUAA-5′ (SEQ ID NO: 707) LDHA-m694 Target:5′-AACGTGAACATCTTCAAGTTCATCATT-3′ (SEQ ID NO: 755)5′-GUGAACAUCUUCAAGUUCAUCAUUC-3′ (SEQ ID NO: 804)3′-UGCACUUGUAGAAGUUCAAGUAGUAAG-5′ (SEQ ID NO: 708) LDHA-m695 Target:5′-ACGTGAACATCTTCAAGTTCATCATTC-3′ (SEQ ID NO: 756)5′-CCGAGUAAUUGGAAGUGGUUGCAAU-3′ (SEQ ID NO: 805)3′-UUGGCUCAUUAACCUUCACCAACGUUA-5′ (SEQ ID NO: 709) LDHA-m823 Target:5′-AACCGAGTAATTGGAAGTGGTTGCAAT-3′ (SEQ ID NO: 757)5′-ACGAGGUGAUCAAGCUGAAAGGUUA-3′ (SEQ ID NO: 806)3′-GAUGCUCCACUAGUUCGACUUUCCAAU-5′ (SEQ ID NO: 710) LDHA-m1071 Target:5′-CTACGAGGTGATCAAGCTGAAAGGTTA-3′ (SEQ ID NO: 758)5′-GCUGAGAGCAUAAUGAAGAACCUUA-3′ (SEQ ID NO: 807)3′-ACCGACUCUCGUAUUACUUCUUGGAAU-5′ (SEQ ID NO: 711) LDHA-m1133 Target:5′-TGGCTGAGAGCATAATGAAGAACCTTA-3′ (SEQ ID NO: 759)5′-GAUUAAGGGUCUCUAUGGAAUCAAU-3′ (SEQ ID NO: 808)3′-UACUAAUUCCCAGAGAUACCUUAGUUA-5′ (SEQ ID NO: 712) LDHA-m1183 Target:5′-ATGATTAAGGGTCTCTATGGAATCAAT-3′ (SEQ ID NO: 760)5′-AAAAUGGAAUCUCGGAUGUUGUGAA-3′ (SEQ ID NO: 809)3′-UGUUUUACCUUAGAGCCUACAACACUU-5′ (SEQ ID NO: 713) LDHA-m1245 Target:5′-ACAAAATGGAATCTCGGATGTTGTGAA-3′ (SEQ ID NO: 761)5′-GGAAUCUCGGAUGUUGUGAAGGUGA-3′ (SEQ ID NO: 810)3′-UACCUUAGAGCCUACAACACUUCCACU-5′ (SEQ ID NO: 714) LDHA-m1250 Target:5′-ATGGAATCTCGGATGTTGTGAAGGTGA-3′ (SEQ ID NO: 762)5′-CGGAUGUUGUGAAGGUGACACUGAC-3′ (SEQ ID NO: 811)3′-GAGCCUACAACACUUCCACUGUGACUG-5′ (SEQ ID NO: 715) LDHA-m1257 Target:5′-CTCGGATGTTGTGAAGGTGACACTGAC-3′ (SEQ ID NO: 763)5′-GAUGCAUAUCUUGUGCAUAAAUGUU-3′ (SEQ ID NO: 812)3′-UACUACGUAUAGAACACGUAUUUACAA-5′ (SEQ ID NO: 716) LDHA-m1687 Target:5′-ATGATGCATATCTTGTGCATAAATGTT-3′ (SEQ ID NO: 764)5′-AUGCAUAUCUUGUGCAUAAAUGUUG-3′ (SEQ ID NO: 813)3′-ACUACGUAUAGAACACGUAUUUACAAC-5′ (SEQ ID NO: 717) LDHA-m1688 Target:5′-TGATGCATATCTTGTGCATAAATGTTG-3′ (SEQ ID NO: 765)5′-GCAUAUCUUGUGCAUAAAUGUUGUA-3′ (SEQ ID NO: 814)3′-UACGUAUAGAACACGUAUUUACAACAU-5′ (SEQ ID NO: 718) LDHA-m1690 Target:5′-ATGCATATCTTGTGCATAAATGTTGTA-3′ (SEQ ID NO: 766)5′-CAUAUCUUGUGCAUAAAUGUUGUAC-3′ (SEQ ID NO: 815)3′-ACGUAUAGAACACGUAUUUACAACAUG-5′ (SEQ ID NO: 719) LDHA-m1691 Target:5′-TGCATATCTTGTGCATAAATGTTGTAC-3′ (SEQ ID NO: 767)5′-AUAUCUUGUGCAUAAAUGUUGUACA-3′ (SEQ ID NO: 816)3′-CGUAUAGAACACGUAUUUACAACAUGU-5′ (SEQ ID NO: 720) LDHA-m1692 Target:5′-GCATATCTTGTGCATAAATGTTGTACA-3′ (SEQ ID NO: 768)5′-AUCUUGUGCAUAAAUGUUGUACAGG-3′ (SEQ ID NO: 817)3′-UAUAGAACACGUAUUUACAACAUGUCC-5′ (SEQ ID NO: 721) LDHA-m1694 Target:5′-ATATCTTGTGCATAAATGTTGTACAGG-3′ (SEQ ID NO: 769)5′-UCUUGUGCAUAAAUGUUGUACAGGA-3′ (SEQ ID NO: 818)3′-AUAGAACACGUAUUUACAACAUGUCCU-5′ (SEQ ID NO: 722) LDHA-m1695 Target:5′-TATCTTGTGCATAAATGTTGTACAGGA-3′ (SEQ ID NO: 770)5′-UUGUGCAUAAAUGUUGUACAGGAUA-3′ (SEQ ID NO: 819)3′-AGAACACGUAUUUACAACAUGUCCUAU-5′ (SEQ ID NO: 723) LDHA-m1697 Target:5′-TCTTGTGCATAAATGTTGTACAGGATA-3′ (SEQ ID NO: 771)5′-UGUGCAUAAAUGUUGUACAGGAUAU-3′ (SEQ ID NO: 820)3′-GAACACGUAUUUACAACAUGUCCUAUA-5′ (SEQ ID NO: 724) LDHA-m1698 Target:5′-CTTGTGCATAAATGTTGTACAGGATAT-3′ (SEQ ID NO: 772)5′-GUGCAUAAAUGUUGUACAGGAUAUU-3′ (SEQ ID NO: 821)3′-AACACGUAUUUACAACAUGUCCUAUAA-5′ (SEQ ID NO: 725) LDHA-m1699 Target:5′-TTGTGCATAAATGTTGTACAGGATATT-3′ (SEQ ID NO: 773)5′-UGCAUAAAUGUUGUACAGGAUAUUU-3′ (SEQ ID NO: 822)3′-ACACGUAUUUACAACAUGUCCUAUAAA-5′ (SEQ ID NO: 726) LDHA-m1700 Target:5′-TGTGCATAAATGTTGTACAGGATATTT-3′ (SEQ ID NO: 774)5′-GCAUAAAUGUUGUACAGGAUAUUUU-3′ (SEQ ID NO: 823)3′-CACGUAUUUACAACAUGUCCUAUAAAA-5′ (SEQ ID NO: 727) LDHA-m1701 Target:5′-GTGCATAAATGTTGTACAGGATATTTT-3′ (SEQ ID NO: 775)5′-CAUAAAUGUUGUACAGGAUAUUUUA-3′ (SEQ ID NO: 824)3′-ACGUAUUUACAACAUGUCCUAUAAAAU-5′ (SEQ ID NO: 728) LDHA-m1702 Target:5′-TGCATAAATGTTGTACAGGATATTTTA-3′ (SEQ ID NO: 776)5′-AUAAAUGUUGUACAGGAUAUUUUAU-3′ (SEQ ID NO: 825)3′-CGUAUUUACAACAUGUCCUAUAAAAUA-5′ (SEQ ID NO: 729) LDHA-m1703 Target:5′-GCATAAATGTTGTACAGGATATTTTAT-3′ (SEQ ID NO: 777)5′-UAAAUGUUGUACAGGAUAUUUUAUA-3′ (SEQ ID NO: 826)3′-GUAUUUACAACAUGUCCUAUAAAAUAU-5′ (SEQ ID NO: 730) LDHA-m1704 Target:5′-CATAAATGTTGTACAGGATATTTTATA-3′ (SEQ ID NO: 778)5′-AAAUGUUGUACAGGAUAUUUUAUAU-3′ (SEQ ID NO: 827)3′-UAUUUACAACAUGUCCUAUAAAAUAUA-5′ (SEQ ID NO: 731) LDHA-m1705 Target:5′-ATAAATGTTGTACAGGATATTTTATAT-3′ (SEQ ID NO: 779)5′-AAUGUUGUACAGGAUAUUUUAUAUA-3′ (SEQ ID NO: 828)3′-AUUUACAACAUGUCCUAUAAAAUAUAU-5′ (SEQ ID NO: 732) LDHA-m1706 Target:5′-TAAATGTTGTACAGGATATTTTATATA-3′ (SEQ ID NO: 780)5′-AUGUUGUACAGGAUAUUUUAUAUAU-3′ (SEQ ID NO: 829)3′-UUUACAACAUGUCCUAUAAAAUAUAUA-5′ (SEQ ID NO: 733) LDHA-m1707 Target:5′-AAATGTTGTACAGGATATTTTATATAT-3′ (SEQ ID NO: 781)5′-UGUUGUACAGGAUAUUUUAUAUAUU-3′ (SEQ ID NO: 830)3′-UUACAACAUGUCCUAUAAAAUAUAUAA-5′ (SEQ ID NO: 734) LDHA-m1708 Target:5′-AATGTTGTACAGGATATTTTATATATT-3′ (SEQ ID NO: 782)5′-GUUGUACAGGAUAUUUUAUAUAUUA-3′ (SEQ ID NO: 831)3′-UACAACAUGUCCUAUAAAAUAUAUAAU-5′ (SEQ ID NO: 735) LDHA-m1709 Target:5′-ATGTTGTACAGGATATTTTATATATTA-3′ (SEQ ID NO: 783)5′-UUGUACAGGAUAUUUUAUAUAUUAU-3′ (SEQ ID NO: 832)3′-ACAACAUGUCCUAUAAAAUAUAUAAUA-5′ (SEQ ID NO: 736) LDHA-m1710 Target:5′-TGTTGTACAGGATATTTTATATATTAT-3′ (SEQ ID NO: 784)5′-GUCUGUAGUGUGCAUUGCAAUAUUA-3′ (SEQ ID NO: 833)3′-CACAGACAUCACACGUAACGUUAUAAU-5′ (SEQ ID NO: 737) LDHA-m1739 Target:5′-GTGTCTGTAGTGTGCATTGCAATATTA-3′ (SEQ ID NO: 785)5′-GUAGUGUGCAUUGCAAUAUUAUGUG-3′ (SEQ ID NO: 834)3′-GACAUCACACGUAACGUUAUAAUACAC-5′ (SEQ ID NO: 738) LDHA-m1743 Target:5′-CTGTAGTGTGCATTGCAATATTATGTG-3′ (SEQ ID NO: 786)5′-UAGUGUGCAUUGCAAUAUUAUGUGA-3′ (SEQ ID NO: 835)3′-ACAUCACACGUAACGUUAUAAUACACU-5′ (SEQ ID NO: 739) LDHA-m1744 Target:5′-TGTAGTGTGCATTGCAATATTATGTGA-3′ (SEQ ID NO: 787)5′-GUGUGCAUUGCAAUAUUAUGUGAGA-3′ (SEQ ID NO: 836)3′-AUCACACGUAACGUUAUAAUACACUCU-5′ (SEQ ID NO: 740) LDHA-m1746 Target:5′-TAGTGTGCATTGCAATATTATGTGAGA-3′ (SEQ ID NO: 788)5′-CAUUGCAAUAUUAUGUGAGAUGUAA-3′ (SEQ ID NO: 837)3′-ACGUAACGUUAUAAUACACUCUACAUU-5′ (SEQ ID NO: 741) LDHA-m1751 Target:5′-TGCATTGCAATATTATGTGAGATGTAA-3′ (SEQ ID NO: 789)5′-AUUGCAAUAUUAUGUGAGAUGUAAG-3′ (SEQ ID NO: 838)3′-CGUAACGUUAUAAUACACUCUACAUUC-5′ (SEQ ID NO: 742) LDHA-m1752 Target:5′-GCATTGCAATATTATGTGAGATGTAAG-3′ (SEQ ID NO: 790)5′-GCAAUAUUAUGUGAGAUGUAAGAUC-3′ (SEQ ID NO: 839)3′-AACGUUAUAAUACACUCUACAUUCUAG-5′ (SEQ ID NO: 743) LDHA-m1755 Target:5′-TTGCAATATTATGTGAGATGTAAGATC-3′ (SEQ ID NO: 791)5′-CAAUAUUAUGUGAGAUGUAAGAUCU-3′ (SEQ ID NO: 840)3′-ACGUUAUAAUACACUCUACAUUCUAGA-5′ (SEQ ID NO: 744) LDHA-m1756 Target:5′-TGCAATATTATGTGAGATGTAAGATCT-3′ (SEQ ID NO: 792)

TABLE 9 DsiRNA Target Sequences (21mers) in Mouse Lactate DehydrogenasemRNA LDHA-m367 21 nt Target: 5′-CUCAAGGACCAGCUGAUUGUG-3′ (SEQ ID NO:841) LDHA-m368 21 nt Target: 5′-UCAAGGACCAGCUGAUUGUGA-3′ (SEQ ID NO:842) LDHA-m372 21 nt Target: 5′-GGACCAGCUGAUUGUGAAUCU-3′ (SEQ ID NO:843) LDHA-m376 21 nt Target: 5′-CAGCUGAUUGUGAAUCUUCUU-3′ (SEQ ID NO:844) LDHA-m456 21 nt Target: 5′-GGCUUGUGCCAUCAGUAUCUU-3′ (SEQ ID NO:845) LDHA-m501 21 nt Target: 5′-UGCCCUUGUUGACGUCAUGGA-3′ (SEQ ID NO:846) LDHA-m506 21 nt Target: 5′-UUGUUGACGUCAUGGAAGACA-3′ (SEQ ID NO:847) LDHA-m507 21 nt Target: 5′-UGUUGACGUCAUGGAAGACAA-3′ (SEQ ID NO:848) LDHA-m584 21 nt Target: 5′-AAAUUGUCUCCAGCAAAGACU-3′ (SEQ ID NO:849) LDHA-m689 21 nt Target: 5′-AGCGAAACGUGAACAUCUUCA-3′ (SEQ ID NO:850) LDHA-m694 21 nt Target: 5′-AACGUGAACAUCUUCAAGUUC-3′ (SEQ ID NO:851) LDHA-m695 21 nt Target: 5′-ACGUGAACAUCUUCAAGUUCA-3′ (SEQ ID NO:852) LDHA-m823 21 nt Target: 5′-AACCGAGUAAUUGGAAGUGGU-3′ (SEQ ID NO:853) LDHA-m1071 21 nt Target: 5′-CUACGAGGUGAUCAAGCUGAA-3′ (SEQ ID NO:854) LDHA-m1133 21 nt Target: 5′-UGGCUGAGAGCAUAAUGAAGA-3′ (SEQ ID NO:855) LDHA-m1183 21 nt Target: 5′-AUGAUUAAGGGUCUCUAUGGA-3′ (SEQ ID NO:856) LDHA-m1245 21 nt Target: 5′-ACAAAAUGGAAUCUCGGAUGU-3′ (SEQ ID NO:857) LDHA-m1250 21 nt Target: 5′-AUGGAAUCUCGGAUGUUGUGA-3′ (SEQ ID NO:858) LDHA-m1257 21 nt Target: 5′-CUCGGAUGUUGUGAAGGUGAC-3′ (SEQ ID NO:859) LDHA-m1687 21 nt Target: 5′-AUGAUGCAUAUCUUGUGCAUA-3′ (SEQ ID NO:860) LDHA-m1688 21 nt Target: 5′-UGAUGCAUAUCUUGUGCAUAA-3′ (SEQ ID NO:861) LDHA-m1690 21 nt Target: 5′-AUGCAUAUCUUGUGCAUAAAU-3′ (SEQ ID NO:862) LDHA-m1691 21 nt Target: 5′-UGCAUAUCUUGUGCAUAAAUG-3′ (SEQ ID NO:863) LDHA-m1692 21 nt Target: 5′-GCAUAUCUUGUGCAUAAAUGU-3′ (SEQ ID NO:864) LDHA-m1694 21 nt Target: 5′-AUAUCUUGUGCAUAAAUGUUG-3′ (SEQ ID NO:865) LDHA-m1695 21 nt Target: 5′-UAUCUUGUGCAUAAAUGUUGU-3′ (SEQ ID NO:866) LDHA-m1697 21 nt Target: 5′-UCUUGUGCAUAAAUGUUGUAC-3′ (SEQ ID NO:867) LDHA-m1698 21 nt Target: 5′-CUUGUGCAUAAAUGUUGUACA-3′ (SEQ ID NO:868) LDHA-m1699 21 nt Target: 5′-UUGUGCAUAAAUGUUGUACAG-3′ (SEQ ID NO:869) LDHA-m1700 21 nt Target: 5′-UGUGCAUAAAUGUUGUACAGG-3′ (SEQ ID NO:870) LDHA-m1701 21 nt Target: 5′-GUGCAUAAAUGUUGUACAGGA-3′ (SEQ ID NO:871) LDHA-m1702 21 nt Target: 5′-UGCAUAAAUGUUGUACAGGAU-3′ (SEQ ID NO:872) LDHA-m1703 21 nt Target: 5′-GCAUAAAUGUUGUACAGGAUA-3′ (SEQ ID NO:873) LDHA-m1704 21 nt Target: 5′-CAUAAAUGUUGUACAGGAUAU-3′ (SEQ ID NO:874) LDHA-m1705 21 nt Target: 5′-AUAAAUGUUGUACAGGAUAUU-3′ (SEQ ID NO:875) LDHA-m1706 21 nt Target: 5′-UAAAUGUUGUACAGGAUAUUU-3′ (SEQ ID NO:876) LDHA-m1707 21 nt Target: 5′-AAAUGUUGUACAGGAUAUUUU-3′ (SEQ ID NO:877) LDHA-m1708 21 nt Target: 5′-AAUGUUGUACAGGAUAUUUUA-3′ (SEQ ID NO:878) LDHA-m1709 21 nt Target: 5′-AUGUUGUACAGGAUAUUUUAU-3′ (SEQ ID NO:879) LDHA-m1710 21 nt Target: 5′-UGUUGUACAGGAUAUUUUAUA-3′ (SEQ ID NO:880) LDHA-m1739 21 nt Target: 5′-GUGUCUGUAGUGUGCAUUGCA-3′ (SEQ ID NO:881) LDHA-m1743 21 nt Target: 5′-CUGUAGUGUGCAUUGCAAUAU-3′ (SEQ ID NO:882) LDHA-m1744 21 nt Target: 5′-UGUAGUGUGCAUUGCAAUAUU-3′ (SEQ ID NO:883) LDHA-m1746 21 nt Target: 5′-UAGUGUGCAUUGCAAUAUUAU-3′ (SEQ ID NO:884) LDHA-m1751 21 nt Target: 5′-UGCAUUGCAAUAUUAUGUGAG-3′ (SEQ ID NO:885) LDHA-m1752 21 nt Target: 5′-GCAUUGCAAUAUUAUGUGAGA-3′ (SEQ ID NO:886) LDHA-m1755 21 nt Target: 5′-UUGCAAUAUUAUGUGAGAUGU-3′ (SEQ ID NO:887) LDHA-m1756 21 nt Target: 5′-UGCAAUAUUAUGUGAGAUGUA-3′ (SEQ ID NO:888)

TABLE 10 Selected Mouse Anti-Lactate Dehydrogenase “Blunt/Blunt” DsiRNAs5′-CUCAAGGACCAGCUGAUUGUGAAUCUU-3′ (SEQ ID NO: 889)3′-GAGUUCCUGGUCGACUAACACUUAGAA-5′ (SEQ ID NO: 697) LDHA-m367 Target:5′-CTCAAGGACCAGCTGATTGTGAATCTT-3′ (SEQ ID NO: 745)5′-UCAAGGACCAGCUGAUUGUGAAUCUUC-3′ (SEQ ID NO: 890)3′-AGUUCCUGGUCGACUAACACUUAGAAG-5′ (SEQ ID NO: 698) LDHA-m368 Target:5′-TCAAGGACCAGCTGATTGTGAATCTTC-3′ (SEQ ID NO: 746)5′-GGACCAGCUGAUUGUGAAUCUUCUUAA-3′ (SEQ ID NO: 891)3′-CCUGGUCGACUAACACUUAGAAGAAUU-5′ (SEQ ID NO: 699) LDHA-m372 Target:5′-GGACCAGCTGATTGTGAATCTTCTTAA-3′ (SEQ ID NO: 747)5′-CAGCUGAUUGUGAAUCUUCUUAAGGAA-3′ (SEQ ID NO: 892)3′-GUCGACUAACACUUAGAAGAAUUCCUU-5′ (SEQ ID NO: 700) LDHA-m376 Target:5′-CAGCTGATTGTGAATCTTCTTAAGGAA-3′ (SEQ ID NO: 748)5′-GGCUUGUGCCAUCAGUAUCUUAAUGAA-3′ (SEQ ID NO: 893)3′-CCGAACACGGUAGUCAUAGAAUUACUU-5′ (SEQ ID NO: 701) LDHA-m456 Target:5′-GGCTTGTGCCATCAGTATCTTAATGAA-3′ (SEQ ID NO: 749)5′-UGCCCUUGUUGACGUCAUGGAAGACAA-3′ (SEQ ID NO: 894)3′-ACGGGAACAACUGCAGUACCUUCUGUU-5′ (SEQ ID NO: 702) LDHA-m501 Target:5′-TGCCCTTGTTGACGTCATGGAAGACAA-3′ (SEQ ID NO: 750)5′-UUGUUGACGUCAUGGAAGACAAACUCA-3′ (SEQ ID NO: 895)3′-AACAACUGCAGUACCUUCUGUUUGAGU-5′ (SEQ ID NO: 703) LDHA-m506 Target:5′-TTGTTGACGTCATGGAAGACAAACTCA-3′ (SEQ ID NO: 751)5′-UGUUGACGUCAUGGAAGACAAACUCAA-3′ (SEQ ID NO: 896)3′-ACAACUGCAGUACCUUCUGUUUGAGUU-5′ (SEQ ID NO: 704) LDHA-m507 Target:5′-TGTTGACGTCATGGAAGACAAACTCAA-3′ (SEQ ID NO: 752)5′-AAAUUGUCUCCAGCAAAGACUACUGUG-3′ (SEQ ID NO: 897)3′-UUUAACAGAGGUCGUUUCUGAUGACAC-5′ (SEQ ID NO: 705) LDHA-m584 Target:5′-AAATTGTCTCCAGCAAAGACTACTGTG-3′ (SEQ ID NO: 753)5′-AGCGAAACGUGAACAUCUUCAAGUUCA-3′ (SEQ ID NO: 898)3′-UCGCUUUGCACUUGUAGAAGUUCAAGU-5′ (SEQ ID NO: 706) LDHA-m689 Target:5′-AGCGAAACGTGAACATCTTCAAGTTCA-3′ (SEQ ID NO: 754)5′-AACGUGAACAUCUUCAAGUUCAUCAUU-3′ (SEQ ID NO: 899)3′-UUGCACUUGUAGAAGUUCAAGUAGUAA-5′ (SEQ ID NO: 707) LDHA-m694 Target:5′-AACGTGAACATCTTCAAGTTCATCATT-3′ (SEQ ID NO: 755)5′-ACGUGAACAUCUUCAAGUUCAUCAUUC-3′ (SEQ ID NO: 900)3′-UGCACUUGUAGAAGUUCAAGUAGUAAG-5′ (SEQ ID NO: 708) LDHA-m695 Target:5′-ACGTGAACATCTTCAAGTTCATCATTC-3′ (SEQ ID NO: 756)5′-AACCGAGUAAUUGGAAGUGGUUGCAAU-3′ (SEQ ID NO: 901)3′-UUGGCUCAUUAACCUUCACCAACGUUA-5′ (SEQ ID NO: 709) LDHA-m823 Target:5′-AACCGAGTAATTGGAAGTGGTTGCAAT-3′ (SEQ ID NO: 757)5′-CUACGAGGUGAUCAAGCUGAAAGGUUA-3′ (SEQ ID NO: 902)3′-GAUGCUCCACUAGUUCGACUUUCCAAU-5′ (SEQ ID NO: 710) LDHA-m1071 Target:5′-CTACGAGGTGATCAAGCTGAAAGGTTA-3′ (SEQ ID NO: 758)5′-UGGCUGAGAGCAUAAUGAAGAACCUUA-3′ (SEQ ID NO: 903)3′-ACCGACUCUCGUAUUACUUCUUGGAAU-5′ (SEQ ID NO: 711) LDHA-m1133 Target:5′-TGGCTGAGAGCATAATGAAGAACCTTA-3′ (SEQ ID NO: 759)5′-AUGAUUAAGGGUCUCUAUGGAAUCAAU-3′ (SEQ ID NO: 904)3′-UACUAAUUCCCAGAGAUACCUUAGUUA-5′ (SEQ ID NO: 712) LDHA-m1183 Target:5′-ATGATTAAGGGTCTCTATGGAATCAAT-3′ (SEQ ID NO: 760)5′-ACAAAAUGGAAUCUCGGAUGUUGUGAA-3′ (SEQ ID NO: 905)3′-UGUUUUACCUUAGAGCCUACAACACUU-5′ (SEQ ID NO: 713) LDHA-m1245 Target:5′-ACAAAATGGAATCTCGGATGTTGTGAA-3′ (SEQ ID NO: 761)5′-AUGGAAUCUCGGAUGUUGUGAAGGUGA-3′ (SEQ ID NO: 906)3′-UACCUUAGAGCCUACAACACUUCCACU-5′ (SEQ ID NO: 714) LDHA-m1250 Target:5′-ATGGAATCTCGGATGTTGTGAAGGTGA-3′ (SEQ ID NO: 762)5′-CUCGGAUGUUGUGAAGGUGACACUGAC-3′ (SEQ ID NO: 907)3′-GAGCCUACAACACUUCCACUGUGACUG-5′ (SEQ ID NO: 715) LDHA-m1257 Target:5′-CTCGGATGTTGTGAAGGTGACACTGAC-3′ (SEQ ID NO: 763)5′-AUGAUGCAUAUCUUGUGCAUAAAUGUU-3′ (SEQ ID NO: 908)3′-UACUACGUAUAGAACACGUAUUUACAA-5′ (SEQ ID NO: 716) LDHA-m1687 Target:5′-ATGATGCATATCTTGTGCATAAATGTT-3′ (SEQ ID NO: 764)5′-UGAUGCAUAUCUUGUGCAUAAAUGUUG-3′ (SEQ ID NO: 909)3′-ACUACGUAUAGAACACGUAUUUACAAC-5′ (SEQ ID NO: 717) LDHA-m1688 Target:5′-TGATGCATATCTTGTGCATAAATGTTG-3′ (SEQ ID NO: 765)5′-AUGCAUAUCUUGUGCAUAAAUGUUGUA-3′ (SEQ ID NO: 910)3′-UACGUAUAGAACACGUAUUUACAACAU-5′ (SEQ ID NO: 718) LDHA-m1690 Target:5′-ATGCATATCTTGTGCATAAATGTTGTA-3′ (SEQ ID NO: 766)5′-UGCAUAUCUUGUGCAUAAAUGUUGUAC-3′ (SEQ ID NO: 911)3′-ACGUAUAGAACACGUAUUUACAACAUG-5′ (SEQ ID NO: 719) LDHA-m1691 Target:5′-TGCATATCTTGTGCATAAATGTTGTAC-3′ (SEQ ID NO: 767)5′-GCAUAUCUUGUGCAUAAAUGUUGUACA-3′ (SEQ ID NO: 912)3′-CGUAUAGAACACGUAUUUACAACAUGU-5′ (SEQ ID NO: 720) LDHA-m1692 Target:5′-GCATATCTTGTGCATAAATGTTGTACA-3′ (SEQ ID NO: 768)5′-AUAUCUUGUGCAUAAAUGUUGUACAGG-3′ (SEQ ID NO: 913)3′-UAUAGAACACGUAUUUACAACAUGUCC-5′ (SEQ ID NO: 721) LDHA-m1694 Target:5′-ATATCTTGTGCATAAATGTTGTACAGG-3′ (SEQ ID NO: 769)5′-UAUCUUGUGCAUAAAUGUUGUACAGGA-3′ (SEQ ID NO: 914)3′-AUAGAACACGUAUUUACAACAUGUCCU-5′ (SEQ ID NO: 722) LDHA-m1695 Target:5′-TATCTTGTGCATAAATGTTGTACAGGA-3′ (SEQ ID NO: 770)5′-UCUUGUGCAUAAAUGUUGUACAGGAUA-3′ (SEQ ID NO: 915)3′-AGAACACGUAUUUACAACAUGUCCUAU-5′ (SEQ ID NO: 723) LDHA-m1697 Target:5′-TCTTGTGCATAAATGTTGTACAGGATA-3′ (SEQ ID NO: 771)5′-CUUGUGCAUAAAUGUUGUACAGGAUAU-3′ (SEQ ID NO: 916)3′-GAACACGUAUUUACAACAUGUCCUAUA-5′ (SEQ ID NO: 724) LDHA-m1698 Target:5′-CTTGTGCATAAATGTTGTACAGGATAT-3′ (SEQ ID NO: 772)5′-UUGUGCAUAAAUGUUGUACAGGAUAUU-3′ (SEQ ID NO: 917)3′-AACACGUAUUUACAACAUGUCCUAUAA-5′ (SEQ ID NO: 725) LDHA-m1699 Target:5′-TTGTGCATAAATGTTGTACAGGATATT-3′ (SEQ ID NO: 773)5′-UGUGCAUAAAUGUUGUACAGGAUAUUU-3′ (SEQ ID NO: 918)3′-ACACGUAUUUACAACAUGUCCUAUAAA-5′ (SEQ ID NO: 726) LDHA-m1700 Target:5′-TGTGCATAAATGTTGTACAGGATATTT-3′ (SEQ ID NO: 774)5′-GUGCAUAAAUGUUGUACAGGAUAUUUU-3′ (SEQ ID NO: 919)3′-CACGUAUUUACAACAUGUCCUAUAAAA-5′ (SEQ ID NO: 727) LDHA-m1701 Target:5′-GTGCATAAATGTTGTACAGGATATTTT-3′ (SEQ ID NO: 775)5′-UGCAUAAAUGUUGUACAGGAUAUUUUA-3′ (SEQ ID NO: 920)3′-ACGUAUUUACAACAUGUCCUAUAAAAU-5′ (SEQ ID NO: 728) LDHA-m1702 Target:5′-TGCATAAATGTTGTACAGGATATTTTA-3′ (SEQ ID NO: 776)5′-GCAUAAAUGUUGUACAGGAUAUUUUAU-3′ (SEQ ID NO: 921)3′-CGUAUUUACAACAUGUCCUAUAAAAUA-5′ (SEQ ID NO: 729) LDHA-m1703 Target:5′-GCATAAATGTTGTACAGGATATTTTAT-3′ (SEQ ID NO: 777)5′-CAUAAAUGUUGUACAGGAUAUUUUAUA-3′ (SEQ ID NO: 922)3′-GUAUUUACAACAUGUCCUAUAAAAUAU-5′ (SEQ ID NO: 730) LDHA-m1704 Target:5′-CATAAATGTTGTACAGGATATTTTATA-3′ (SEQ ID NO: 778)5′-AUAAAUGUUGUACAGGAUAUUUUAUAU-3′ (SEQ ID NO: 923)3′-UAUUUACAACAUGUCCUAUAAAAUAUA-5′ (SEQ ID NO: 731) LDHA-m1705 Target:5′-ATAAATGTTGTACAGGATATTTTATAT-3′ (SEQ ID NO: 779)5′-UAAAUGUUGUACAGGAUAUUUUAUAUA-3′ (SEQ ID NO: 924)3′-AUUUACAACAUGUCCUAUAAAAUAUAU-5′ (SEQ ID NO: 732) LDHA-m1706 Target:5′-TAAATGTTGTACAGGATATTTTATATA-3′ (SEQ ID NO: 780)5′-AAAUGUUGUACAGGAUAUUUUAUAUAU-3′ (SEQ ID NO: 925)3′-UUUACAACAUGUCCUAUAAAAUAUAUA-5′ (SEQ ID NO: 733) LDHA-m1707 Target:5′-AAATGTTGTACAGGATATTTTATATAT-3′ (SEQ ID NO: 781)5′-AAUGUUGUACAGGAUAUUUUAUAUAUU-3′ (SEQ ID NO: 926)3′-UUACAACAUGUCCUAUAAAAUAUAUAA-5′ (SEQ ID NO: 734) LDHA-m1708 Target:5′-AATGTTGTACAGGATATTTTATATATT-3′ (SEQ ID NO: 782)5′-AUGUUGUACAGGAUAUUUUAUAUAUUA-3′ (SEQ ID NO: 927)3′-UACAACAUGUCCUAUAAAAUAUAUAAU-5′ (SEQ ID NO: 735) LDHA-m1709 Target:5′-ATGTTGTACAGGATATTTTATATATTA-3′ (SEQ ID NO: 783)5′-UGUUGUACAGGAUAUUUUAUAUAUUAU-3′ (SEQ ID NO: 928)3′-ACAACAUGUCCUAUAAAAUAUAUAAUA-5′ (SEQ ID NO: 736) LDHA-m1710 Target:5′-TGTTGTACAGGATATTTTATATATTAT-3′ (SEQ ID NO: 784)5′-GUGUCUGUAGUGUGCAUUGCAAUAUUA-3′ (SEQ ID NO: 929)3′-CACAGACAUCACACGUAACGUUAUAAU-5′ (SEQ ID NO: 737) LDHA-m1739 Target:5′-GTGTCTGTAGTGTGCATTGCAATATTA-3′ (SEQ ID NO: 785)5′-CUGUAGUGUGCAUUGCAAUAUUAUGUG-3′ (SEQ ID NO: 930)3′-GACAUCACACGUAACGUUAUAAUACAC-5′ (SEQ ID NO: 738) LDHA-m1743 Target:5′-CTGTAGTGTGCATTGCAATATTATGTG-3′ (SEQ ID NO: 786)5′-UGUAGUGUGCAUUGCAAUAUUAUGUGA-3′ (SEQ ID NO: 931)3′-ACAUCACACGUAACGUUAUAAUACACU-5′ (SEQ ID NO: 739) LDHA-m1744 Target:5′-TGTAGTGTGCATTGCAATATTATGTGA-3′ (SEQ ID NO: 787)5′-UAGUGUGCAUUGCAAUAUUAUGUGAGA-3′ (SEQ ID NO: 932)3′-AUCACACGUAACGUUAUAAUACACUCU-5′ (SEQ ID NO: 740) LDHA-m1746 Target:5′-TAGTGTGCATTGCAATATTATGTGAGA-3′ (SEQ ID NO: 788)5′-UGCAUUGCAAUAUUAUGUGAGAUGUAA-3′ (SEQ ID NO: 933)3′-ACGUAACGUUAUAAUACACUCUACAUU-5′ (SEQ ID NO: 741) LDHA-m1751 Target:5′-TGCATTGCAATATTATGTGAGATGTAA-3′ (SEQ ID NO: 789)5′-GCAUUGCAAUAUUAUGUGAGAUGUAAG-3′ (SEQ ID NO: 934)3′-CGUAACGUUAUAAUACACUCUACAUUC-5′ (SEQ ID NO: 742) LDHA-m1752 Target:5′-GCATTGCAATATTATGTGAGATGTAAG-3′ (SEQ ID NO: 790)5′-UUGCAAUAUUAUGUGAGAUGUAAGAUC-3′ (SEQ ID NO: 935)3′-AACGUUAUAAUACACUCUACAUUCUAG-5′ (SEQ ID NO: 743) LDHA-m1755 Target:5′-TTGCAATATTATGTGAGATGTAAGATC-3′ (SEQ ID NO: 791)5′-UGCAAUAUUAUGUGAGAUGUAAGAUCU-3′ (SEQ ID NO: 936)3′-ACGUUAUAAUACACUCUACAUUCUAGA-5′ (SEQ ID NO: 744) LDHA-m1756 Target:5′-TGCAATATTATGTGAGATGTAAGATCT-3′ (SEQ ID NO: 792)

TABLE 11 DsiRNA Component 19 Nucleotide Target Sequences in MouseLactate Dehydrogenase mRNA LDHA-m367 19 nt Target #1:5′-CAAGGACCAGCUGAUUGUG-3′ (SEQ ID NO: 937) LDHA-m367 19 nt Target #2:5′-UCAAGGACCAGCUGAUUGU-3′ (SEQ ID NO: 985) LDHA-m367 19 nt Target #3:5′-CUCAAGGACCAGCUGAUUG-3′ (SEQ ID NO: 1033) LDHA-m368 19 nt Target #1:5′-AAGGACCAGCUGAUUGUGA-3′ (SEQ ID NO: 938) LDHA-m368 19 nt Target #2:5′-CAAGGACCAGCUGAUUGUG-3′ (SEQ ID NO: 986) LDHA-m368 19 nt Target #3:5′-UCAAGGACCAGCUGAUUGU-3′ (SEQ ID NO: 1034) LDHA-m372 19 nt Target #1:5′-ACCAGCUGAUUGUGAAUCU-3′ (SEQ ID NO: 939) LDHA-m372 19 nt Target #2:5′-GACCAGCUGAUUGUGAAUC-3′ (SEQ ID NO: 987) LDHA-m372 19 nt Target #3:5′-GGACCAGCUGAUUGUGAAU-3′ (SEQ ID NO: 1035) LDHA-m376 19 nt Target #1:5′-GCUGAUUGUGAAUCUUCUU-3′ (SEQ ID NO: 940) LDHA-m376 19 nt Target #2:5′-AGCUGAUUGUGAAUCUUCU-3′ (SEQ ID NO: 988) LDHA-m376 19 nt Target #3:5′-CAGCUGAUUGUGAAUCUUC-3′ (SEQ ID NO: 1036) LDHA-m456 19 nt Target #1:5′-CUUGUGCCAUCAGUAUCUU-3′ (SEQ ID NO: 941) LDHA-m456 19 nt Target #2:5′-GCUUGUGCCAUCAGUAUCU-3′ (SEQ ID NO: 989) LDHA-m456 19 nt Target #3:5′-GGCUUGUGCCAUCAGUAUC-3′ (SEQ ID NO: 1037) LDHA-m501 19 nt Target #1:5′-CCCUUGUUGACGUCAUGGA-3′ (SEQ ID NO: 942) LDHA-m501 19 nt Target #2:5′-GCCCUUGUUGACGUCAUGG-3′ (SEQ ID NO: 990) LDHA-m501 19 nt Target #3:5′-UGCCCUUGUUGACGUCAUG-3′ (SEQ ID NO: 1038) LDHA-m506 19 nt Target #1:5′-GUUGACGUCAUGGAAGACA-3′ (SEQ ID NO: 943) LDHA-m506 19 nt Target #2:5′-UGUUGACGUCAUGGAAGAC-3′ (SEQ ID NO: 991) LDHA-m506 19 nt Target #3:5′-UUGUUGACGUCAUGGAAGA-3′ (SEQ ID NO: 1039) LDHA-m507 19 nt Target #1:5′-UUGACGUCAUGGAAGACAA-3′ (SEQ ID NO: 944) LDHA-m507 19 nt Target #2:5′-GUUGACGUCAUGGAAGACA-3′ (SEQ ID NO: 992) LDHA-m507 19 nt Target #3:5′-UGUUGACGUCAUGGAAGAC-3′ (SEQ ID NO: 1040) LDHA-m584 19 nt Target #1:5′-AUUGUCUCCAGCAAAGACU-3′ (SEQ ID NO: 945) LDHA-m584 19 nt Target #2:5′-AAUUGUCUCCAGCAAAGAC-3′ (SEQ ID NO: 993) LDHA-m584 19 nt Target #3:5′-AAAUUGUCUCCAGCAAAGA-3′ (SEQ ID NO: 1041) LDHA-m689 19 nt Target #1:5′-CGAAACGUGAACAUCUUCA-3′ (SEQ ID NO: 946) LDHA-m689 19 nt Target #2:5′-GCGAAACGUGAACAUCUUC-3′ (SEQ ID NO: 994) LDHA-m689 19 nt Target #3:5′-AGCGAAACGUGAACAUCUU-3′ (SEQ ID NO: 1042) LDHA-m694 19 nt Target #1:5′-CGUGAACAUCUUCAAGUUC-3′ (SEQ ID NO: 947) LDHA-m694 19 nt Target #2:5′-ACGUGAACAUCUUCAAGUU-3′ (SEQ ID NO: 995) LDHA-m694 19 nt Target #3:5′-AACGUGAACAUCUUCAAGU-3′ (SEQ ID NO: 1043) LDHA-m695 19 nt Target #1:5′-GUGAACAUCUUCAAGUUCA-3′ (SEQ ID NO: 948) LDHA-m695 19 nt Target #2:5′-CGUGAACAUCUUCAAGUUC-3′ (SEQ ID NO: 996) LDHA-m695 19 nt Target #3:5′-ACGUGAACAUCUUCAAGUU-3′ (SEQ ID NO: 1044) LDHA-m823 19 nt Target #1:5′-CCGAGUAAUUGGAAGUGGU-3′ (SEQ ID NO: 949) LDHA-m823 19 nt Target #2:5′-ACCGAGUAAUUGGAAGUGG-3′ (SEQ ID NO: 997) LDHA-m823 19 nt Target #3:5′-AACCGAGUAAUUGGAAGUG-3′ (SEQ ID NO: 1045) LDHA-m1071 19 nt Target #1:5′-ACGAGGUGAUCAAGCUGAA-3′ (SEQ ID NO: 950) LDHA-m1071 19 nt Target #2:5′-UACGAGGUGAUCAAGCUGA-3′ (SEQ ID NO: 998) LDHA-m1071 19 nt Target #3:5′-CUACGAGGUGAUCAAGCUG-3′ (SEQ ID NO: 1046) LDHA-m1133 19 nt Target #1:5′-GCUGAGAGCAUAAUGAAGA-3′ (SEQ ID NO: 951) LDHA-m1133 19 nt Target #2:5′-GGCUGAGAGCAUAAUGAAG-3′ (SEQ ID NO: 999) LDHA-m1133 19 nt Target #3:5′-UGGCUGAGAGCAUAAUGAA-3′ (SEQ ID NO: 1047) LDHA-m1183 19 nt Target #1:5′-GAUUAAGGGUCUCUAUGGA-3′ (SEQ ID NO: 952) LDHA-m1183 19 nt Target #2:5′-UGAUUAAGGGUCUCUAUGG-3′ (SEQ ID NO: 1000) LDHA-m1183 19 nt Target #3:5′-AUGAUUAAGGGUCUCUAUG-3′ (SEQ ID NO: 1048) LDHA-m1245 19 nt Target #1:5′-AAAAUGGAAUCUCGGAUGU-3′ (SEQ ID NO: 953) LDHA-m1245 19 nt Target #2:5′-CAAAAUGGAAUCUCGGAUG-3′ (SEQ ID NO: 1001) LDHA-m1245 19 nt Target #3:5′-ACAAAAUGGAAUCUCGGAU-3′ (SEQ ID NO: 1049) LDHA-m1250 19 nt Target #1:5′-GGAAUCUCGGAUGUUGUGA-3′ (SEQ ID NO: 954) LDHA-m1250 19 nt Target #2:5′-UGGAAUCUCGGAUGUUGUG-3′ (SEQ ID NO: 1002) LDHA-m1250 19 nt Target #3:5′-AUGGAAUCUCGGAUGUUGU-3′ (SEQ ID NO: 1050) LDHA-m1257 19 nt Target #1:5′-CGGAUGUUGUGAAGGUGAC-3′ (SEQ ID NO: 955) LDHA-m1257 19 nt Target #2:5′-UCGGAUGUUGUGAAGGUGA-3′ (SEQ ID NO: 1003) LDHA-m1257 19 nt Target #3:5′-CUCGGAUGUUGUGAAGGUG-3′ (SEQ ID NO: 1051) LDHA-m1687 19 nt Target #1:5′-GAUGCAUAUCUUGUGCAUA-3′ (SEQ ID NO: 956) LDHA-m1687 19 nt Target #2:5′-UGAUGCAUAUCUUGUGCAU-3′ (SEQ ID NO: 1004) LDHA-m1687 19 nt Target #3:5′-AUGAUGCAUAUCUUGUGCA-3′ (SEQ ID NO: 1052) LDHA-m1688 19 nt Target #1:5′-AUGCAUAUCUUGUGCAUAA-3′ (SEQ ID NO: 957) LDHA-m1688 19 nt Target #2:5′-GAUGCAUAUCUUGUGCAUA-3′ (SEQ ID NO: 1005) LDHA-m1688 19 nt Target #3:5′-UGAUGCAUAUCUUGUGCAU-3′ (SEQ ID NO: 1053) LDHA-m1690 19 nt Target #1:5′-GCAUAUCUUGUGCAUAAAU-3′ (SEQ ID NO: 958) LDHA-m1690 19 nt Target #2:5′-UGCAUAUCUUGUGCAUAAA-3′ (SEQ ID NO: 1006) LDHA-m1690 19 nt Target #3:5′-AUGCAUAUCUUGUGCAUAA-3′ (SEQ ID NO: 1054) LDHA-m1691 19 nt Target #1:5′-CAUAUCUUGUGCAUAAAUG-3′ (SEQ ID NO: 959) LDHA-m1691 19 nt Target #2:5′-GCAUAUCUUGUGCAUAAAU-3′ (SEQ ID NO: 1007) LDHA-m1691 19 nt Target #3:5′-UGCAUAUCUUGUGCAUAAA-3′ (SEQ ID NO: 1055) LDHA-m1692 19 nt Target #1:5′-AUAUCUUGUGCAUAAAUGU-3′ (SEQ ID NO: 960) LDHA-m1692 19 nt Target #2:5′-CAUAUCUUGUGCAUAAAUG-3′ (SEQ ID NO: 1008) LDHA-m1692 19 nt Target #3:5′-GCAUAUCUUGUGCAUAAAU-3′ (SEQ ID NO: 1056) LDHA-m1694 19 nt Target #1:5′-AUCUUGUGCAUAAAUGUUG-3′ (SEQ ID NO: 961) LDHA-m1694 19 nt Target #2:5′-UAUCUUGUGCAUAAAUGUU-3′ (SEQ ID NO: 1009) LDHA-m1694 19 nt Target #3:5′-AUAUCUUGUGCAUAAAUGU-3′ (SEQ ID NO: 1057) LDHA-m1695 19 nt Target #1:5′-UCUUGUGCAUAAAUGUUGU-3′ (SEQ ID NO: 962) LDHA-m1695 19 nt Target #2:5′-AUCUUGUGCAUAAAUGUUG-3′ (SEQ ID NO: 1010) LDHA-m1695 19 nt Target #3:5′-UAUCUUGUGCAUAAAUGUU-3′ (SEQ ID NO: 1058) LDHA-m1697 19 nt Target #1:5′-UUGUGCAUAAAUGUUGUAC-3′ (SEQ ID NO: 963) LDHA-m1697 19 nt Target #2:5′-CUUGUGCAUAAAUGUUGUA-3′ (SEQ ID NO: 1011) LDHA-m1697 19 nt Target #3:5′-UCUUGUGCAUAAAUGUUGU-3′ (SEQ ID NO: 1059) LDHA-m1698 19 nt Target #1:5′-UGUGCAUAAAUGUUGUACA-3′ (SEQ ID NO: 964) LDHA-m1698 19 nt Target #2:5′-UUGUGCAUAAAUGUUGUAC-3′ (SEQ ID NO: 1012) LDHA-m1698 19 nt Target #3:5′-CUUGUGCAUAAAUGUUGUA-3′ (SEQ ID NO: 1060) LDHA-m1699 19 nt Target #1:5′-GUGCAUAAAUGUUGUACAG-3′ (SEQ ID NO: 965) LDHA-m1699 19 nt Target #2:5′-UGUGCAUAAAUGUUGUACA-3′ (SEQ ID NO: 1013) LDHA-m1699 19 nt Target #3:5′-UUGUGCAUAAAUGUUGUAC-3′ (SEQ ID NO: 1061) LDHA-m1700 19 nt Target #1:5′-UGCAUAAAUGUUGUACAGG-3′ (SEQ ID NO: 966) LDHA-m1700 19 nt Target #2:5′-GUGCAUAAAUGUUGUACAG-3′ (SEQ ID NO: 1014) LDHA-m1700 19 nt Target #3:5′-UGUGCAUAAAUGUUGUACA-3′ (SEQ ID NO: 1062) LDHA-m1701 19 nt Target #1:5′-GCAUAAAUGUUGUACAGGA-3′ (SEQ ID NO: 967) LDHA-m1701 19 nt Target #2:5′-UGCAUAAAUGUUGUACAGG-3′ (SEQ ID NO: 1015) LDHA-m1701 19 nt Target #3:5′-GUGCAUAAAUGUUGUACAG-3′ (SEQ ID NO: 1063) LDHA-m1702 19 nt Target #1:5′-CAUAAAUGUUGUACAGGAU-3′ (SEQ ID NO: 968) LDHA-m1702 19 nt Target #2:5′-GCAUAAAUGUUGUACAGGA-3′ (SEQ ID NO: 1016) LDHA-m1702 19 nt Target #3:5′-UGCAUAAAUGUUGUACAGG-3′ (SEQ ID NO: 1064) LDHA-m1703 19 nt Target #1:5′-AUAAAUGUUGUACAGGAUA-3′ (SEQ ID NO: 969) LDHA-m1703 19 nt Target #2:5′-CAUAAAUGUUGUACAGGAU-3′ (SEQ ID NO: 1017) LDHA-m1703 19 nt Target #3:5′-GCAUAAAUGUUGUACAGGA-3′ (SEQ ID NO: 1065) LDHA-m1704 19 nt Target #1:5′-UAAAUGUUGUACAGGAUAU-3′ (SEQ ID NO: 970) LDHA-m1704 19 nt Target #2:5′-AUAAAUGUUGUACAGGAUA-3′ (SEQ ID NO: 1018) LDHA-m1704 19 nt Target #3:5′-CAUAAAUGUUGUACAGGAU-3′ (SEQ ID NO: 1066) LDHA-m1705 19 nt Target #1:5′-AAAUGUUGUACAGGAUAUU-3′ (SEQ ID NO: 971) LDHA-m1705 19 nt Target #2:5′-UAAAUGUUGUACAGGAUAU-3′ (SEQ ID NO: 1019) LDHA-m1705 19 nt Target #3:5′-AUAAAUGUUGUACAGGAUA-3′ (SEQ ID NO: 1067) LDHA-m1706 19 nt Target #1:5′-AAUGUUGUACAGGAUAUUU-3′ (SEQ ID NO: 972) LDHA-m1706 19 nt Target #2:5′-AAAUGUUGUACAGGAUAUU-3′ (SEQ ID NO: 1020) LDHA-m1706 19 nt Target #3:5′-UAAAUGUUGUACAGGAUAU-3′ (SEQ ID NO: 1068) LDHA-m1707 19 nt Target #1:5′-AUGUUGUACAGGAUAUUUU-3′ (SEQ ID NO: 973) LDHA-m1707 19 nt Target #2:5′-AAUGUUGUACAGGAUAUUU-3′ (SEQ ID NO: 1021) LDHA-m1707 19 nt Target #3:5′-AAAUGUUGUACAGGAUAUU-3′ (SEQ ID NO: 1069) LDHA-m1708 19 nt Target #1:5′-UGUUGUACAGGAUAUUUUA-3′ (SEQ ID NO: 974) LDHA-m1708 19 nt Target #2:5′-AUGUUGUACAGGAUAUUUU-3′ (SEQ ID NO: 1022) LDHA-m1708 19 nt Target #3:5′-AAUGUUGUACAGGAUAUUU-3′ (SEQ ID NO: 1070) LDHA-m1709 19 nt Target #1:5′-GUUGUACAGGAUAUUUUAU-3′ (SEQ ID NO: 975) LDHA-m1709 19 nt Target #2:5′-UGUUGUACAGGAUAUUUUA-3′ (SEQ ID NO: 1023) LDHA-m1709 19 nt Target #3:5′-AUGUUGUACAGGAUAUUUU-3′ (SEQ ID NO: 1071) LDHA-m1710 19 nt Target #1:5′-UUGUACAGGAUAUUUUAUA-3′ (SEQ ID NO: 976) LDHA-m1710 19 nt Target #2:5′-GUUGUACAGGAUAUUUUAU-3′ (SEQ ID NO: 1024) LDHA-m1710 19 nt Target #3:5′-UGUUGUACAGGAUAUUUUA-3′ (SEQ ID NO: 1072) LDHA-m1739 19 nt Target #1:5′-GUCUGUAGUGUGCAUUGCA-3′ (SEQ ID NO: 977) LDHA-m1739 19 nt Target #2:5′-UGUCUGUAGUGUGCAUUGC-3′ (SEQ ID NO: 1025) LDHA-m1739 19 nt Target #3:5′-GUGUCUGUAGUGUGCAUUG-3′ (SEQ ID NO: 1073) LDHA-m1743 19 nt Target #1:5′-GUAGUGUGCAUUGCAAUAU-3′ (SEQ ID NO: 978) LDHA-m1743 19 nt Target #2:5′-UGUAGUGUGCAUUGCAAUA-3′ (SEQ ID NO: 1026) LDHA-m1743 19 nt Target #3:5′-CUGUAGUGUGCAUUGCAAU-3′ (SEQ ID NO: 1074) LDHA-m1744 19 nt Target #1:5′-UAGUGUGCAUUGCAAUAUU-3′ (SEQ ID NO: 979) LDHA-m1744 19 nt Target #2:5′-GUAGUGUGCAUUGCAAUAU-3′ (SEQ ID NO: 1027) LDHA-m1744 19 nt Target #3:5′-UGUAGUGUGCAUUGCAAUA-3′ (SEQ ID NO: 1075) LDHA-m1746 19 nt Target #1:5′-GUGUGCAUUGCAAUAUUAU-3′ (SEQ ID NO: 980) LDHA-m1746 19 nt Target #2:5′-AGUGUGCAUUGCAAUAUUA-3′ (SEQ ID NO: 1028) LDHA-m1746 19 nt Target #3:5′-UAGUGUGCAUUGCAAUAUU-3′ (SEQ ID NO: 1076) LDHA-m1751 19 nt Target #1:5′-CAUUGCAAUAUUAUGUGAG-3′ (SEQ ID NO: 981) LDHA-m1751 19 nt Target #2:5′-GCAUUGCAAUAUUAUGUGA-3′ (SEQ ID NO: 1029) LDHA-m1751 19 nt Target #3:5′-UGCAUUGCAAUAUUAUGUG-3′ (SEQ ID NO: 1077) LDHA-m1752 19 nt Target #1:5′-AUUGCAAUAUUAUGUGAGA-3′ (SEQ ID NO: 982) LDHA-m1752 19 nt Target #2:5′-CAUUGCAAUAUUAUGUGAG-3′ (SEQ ID NO: 1030) LDHA-m1752 19 nt Target #3:5′-GCAUUGCAAUAUUAUGUGA-3′ (SEQ ID NO: 1078) LDHA-m1755 19 nt Target #1:5′-GCAAUAUUAUGUGAGAUGU-3′ (SEQ ID NO: 983) LDHA-m1755 19 nt Target #2:5′-UGCAAUAUUAUGUGAGAUG-3′ (SEQ ID NO: 1031) LDHA-m1755 19 nt Target #3:5′-UUGCAAUAUUAUGUGAGAU-3′ (SEQ ID NO: 1079) LDHA-m1756 19 nt Target #1:5′-CAAUAUUAUGUGAGAUGUA-3′ (SEQ ID NO: 984) LDHA-m1756 19 nt Target #2:5′-GCAAUAUUAUGUGAGAUGU-3′ (SEQ ID NO: 1032) LDHA-m1756 19 nt Target #3:5′-UGCAAUAUUAUGUGAGAUG-3′ (SEQ ID NO: 1080)

TABLE 12 Additional Selected Human Anti-Lactate Dehydrogenase DsiRNAAgents (Asymmetrics) 5′-CUGCCGGUCGGUUGUCUGGCUGCgc-3′ (SEQ ID NO: 1081)3′-CAGACGGCCAGCCAACAGACCGACGCG-5′ (SEQ ID NO: 3095) LDHA-27 Target:5′-GTCTGCCGGTCGGTTGTCTGGCTGCGC-3′ (SEQ ID NO: 5109)5′-UGCCGGUCGGUUGUCUGGCUGCGcg-3′ (SEQ ID NO: 1082)3′-AGACGGCCAGCCAACAGACCGACGCGC-5′ (SEQ ID NO: 3096) LDHA-28 Target:5′-TCTGCCGGTCGGTTGTCTGGCTGCGCG-3′ (SEQ ID NO: 5110)5′-GCCGGUCGGUUGUCUGGCUGCGCgc-3′ (SEQ ID NO: 1083)3′-GACGGCCAGCCAACAGACCGACGCGCG-5′ (SEQ ID NO: 3097) LDHA-29 Target:5′-CTGCCGGTCGGTTGTCTGGCTGCGCGC-3′ (SEQ ID NO: 5111)5′-GUCGGUUGUCUGGCUGCGCGCGCca-3′ (SEQ ID NO: 1084)3′-GCCAGCCAACAGACCGACGCGCGCGGU-5′ (SEQ ID NO: 3098) LDHA-33 Target:5′-CGGTCGGTTGTCTGGCTGCGCGCGCCA-3′ (SEQ ID NO: 5112)5′-GUGCCCCGCCUGGCUCGGCAUCCac-3′ (SEQ ID NO: 1085)3′-GUCACGGGGCGGACCGAGCCGUAGGUG-5′ (SEQ ID NO: 3099) LDHA-72 Target:5′-CAGTGCCCCGCCTGGCTCGGCATCCAC-3′ (SEQ ID NO: 5113)5′-CCGCCUGGCUCGGCAUCCACCCCca-3′ (SEQ ID NO: 1086)3′-GGGGCGGACCGAGCCGUAGGUGGGGGU-5′ (SEQ ID NO: 3100) LDHA-77 Target:5′-CCCCGCCTGGCTCGGCATCCACCCCCA-3′ (SEQ ID NO: 5114)5′-CGCCUGGCUCGGCAUCCACCCCCag-3′ (SEQ ID NO: 1087)3′-GGGCGGACCGAGCCGUAGGUGGGGGUC-5′ (SEQ ID NO: 3101) LDHA-78 Target:5′-CCCGCCTGGCTCGGCATCCACCCCCAG-3′ (SEQ ID NO: 5115)5′-CCUGGCUCGGCAUCCACCCCCAGcc-3′ (SEQ ID NO: 1088)3′-GCGGACCGAGCCGUAGGUGGGGGUCGG-5′ (SEQ ID NO: 3102) LDHA-80 Target:5′-CGCCTGGCTCGGCATCCACCCCCAGCC-3′ (SEQ ID NO: 5116)5′-UGGCUCGGCAUCCACCCCCAGCCcg-3′ (SEQ ID NO: 1089)3′-GGACCGAGCCGUAGGUGGGGGUCGGGC-5′ (SEQ ID NO: 3103) LDHA-82 Target:5′-CCTGGCTCGGCATCCACCCCCAGCCCG-3′ (SEQ ID NO: 5117)5′-GGCUCGGCAUCCACCCCCAGCCCga-3′ (SEQ ID NO: 1090)3′-GACCGAGCCGUAGGUGGGGGUCGGGCU-5′ (SEQ ID NO: 3104) LDHA-83 Target:5′-CTGGCTCGGCATCCACCCCCAGCCCGA-3′ (SEQ ID NO: 5118)5′-GCUCGGCAUCCACCCCCAGCCCGac-3′ (SEQ ID NO: 1091)3′-ACCGAGCCGUAGGUGGGGGUCGGGCUG-5′ (SEQ ID NO: 3105) LDHA-84 Target:5′-TGGCTCGGCATCCACCCCCAGCCCGAC-3′ (SEQ ID NO: 5119)5′-CUCGGCAUCCACCCCCAGCCCGAct-3′ (SEQ ID NO: 1092)3′-CCGAGCCGUAGGUGGGGGUCGGGCUGA-5′ (SEQ ID NO: 3106) LDHA-85 Target:5′-GGCTCGGCATCCACCCCCAGCCCGACT-3′ (SEQ ID NO: 5120)5′-UCGGCAUCCACCCCCAGCCCGACtc-3′ (SEQ ID NO: 1093)3′-CGAGCCGUAGGUGGGGGUCGGGCUGAG-5′ (SEQ ID NO: 3107) LDHA-86 Target:5′-GCTCGGCATCCACCCCCAGCCCGACTC-3′ (SEQ ID NO: 5121)5′-CGGCAUCCACCCCCAGCCCGACUca-3′ (SEQ ID NO: 1094)3′-GAGCCGUAGGUGGGGGUCGGGCUGAGU-5′ (SEQ ID NO: 3108) LDHA-87 Target:5′-CTCGGCATCCACCCCCAGCCCGACTCA-3′ (SEQ ID NO: 5122)5′-GGCAUCCACCCCCAGCCCGACUCac-3′ (SEQ ID NO: 1095)3′-AGCCGUAGGUGGGGGUCGGGCUGAGUG-5′ (SEQ ID NO: 3109) LDHA-88 Target:5′-TCGGCATCCACCCCCAGCCCGACTCAC-3′ (SEQ ID NO: 5123)5′-GCAUCCACCCCCAGCCCGACUCAca-3′ (SEQ ID NO: 1096)3′-GCCGUAGGUGGGGGUCGGGCUGAGUGU-5′ (SEQ ID NO: 3110) LDHA-89 Target:5′-CGGCATCCACCCCCAGCCCGACTCACA-3′ (SEQ ID NO: 5124)5′-CAUCCACCCCCAGCCCGACUCACac-3′ (SEQ ID NO: 1097)3′-CCGUAGGUGGGGGUCGGGCUGAGUGUG-5′ (SEQ ID NO: 3111) LDHA-90 Target:5′-GGCATCCACCCCCAGCCCGACTCACAC-3′ (SEQ ID NO: 5125)5′-AUCCACCCCCAGCCCGACUCACAcg-3′ (SEQ ID NO: 1098)3′-CGUAGGUGGGGGUCGGGCUGAGUGUGC-5′ (SEQ ID NO: 3112) LDHA-91 Target:5′-GCATCCACCCCCAGCCCGACTCACACG-3′ (SEQ ID NO: 5126)5′-UCCACCCCCAGCCCGACUCACACgt-3′ (SEQ ID NO: 1099)3′-GUAGGUGGGGGUCGGGCUGAGUGUGCA-5′ (SEQ ID NO: 3113) LDHA-92 Target:5′-CATCCACCCCCAGCCCGACTCACACGT-3′ (SEQ ID NO: 5127)5′-CCACCCCCAGCCCGACUCACACGtg-3′ (SEQ ID NO: 1100)3′-UAGGUGGGGGUCGGGCUGAGUGUGCAC-5′ (SEQ ID NO: 3114) LDHA-93 Target:5′-ATCCACCCCCAGCCCGACTCACACGTG-3′ (SEQ ID NO: 5128)5′-CACCCCCAGCCCGACUCACACGUgg-3′ (SEQ ID NO: 1101)3′-AGGUGGGGGUCGGGCUGAGUGUGCACC-5′ (SEQ ID NO: 3115) LDHA-94 Target:5′-TCCACCCCCAGCCCGACTCACACGTGG-3′ (SEQ ID NO: 5129)5′-ACCCCCAGCCCGACUCACACGUGgg-3′ (SEQ ID NO: 1102)3′-GGUGGGGGUCGGGCUGAGUGUGCACCC-5′ (SEQ ID NO: 3116) LDHA-95 Target:5′-CCACCCCCAGCCCGACTCACACGTGGG-3′ (SEQ ID NO: 5130)5′-CCCCCAGCCCGACUCACACGUGGgt-3′ (SEQ ID NO: 1103)3′-GUGGGGGUCGGGCUGAGUGUGCACCCA-5′ (SEQ ID NO: 3117) LDHA-96 Target:5′-CACCCCCAGCCCGACTCACACGTGGGT-3′ (SEQ ID NO: 5131)5′-CCCCAGCCCGACUCACACGUGGGtt-3′ (SEQ ID NO: 1104)3′-UGGGGGUCGGGCUGAGUGUGCACCCAA-5′ (SEQ ID NO: 3118) LDHA-97 Target:5′-ACCCCCAGCCCGACTCACACGTGGGTT-3′ (SEQ ID NO: 5132)5′-CCCAGCCCGACUCACACGUGGGUtc-3′ (SEQ ID NO: 1105)3′-GGGGGUCGGGCUGAGUGUGCACCCAAG-5′ (SEQ ID NO: 3119) LDHA-98 Target:5′-CCCCCAGCCCGACTCACACGTGGGTTC-3′ (SEQ ID NO: 5133)5′-CCAGCCCGACUCACACGUGGGUUcc-3′ (SEQ ID NO: 1106)3′-GGGGUCGGGCUGAGUGUGCACCCAAGG-5′ (SEQ ID NO: 3120) LDHA-99 Target:5′-CCCCAGCCCGACTCACACGTGGGTTCC-3′ (SEQ ID NO: 5134)5′-CAGCCCGACUCACACGUGGGUUCcc-3′ (SEQ ID NO: 1107)3′-GGGUCGGGCUGAGUGUGCACCCAAGGG-5′ (SEQ ID NO: 3121) LDHA-100 Target:5′-CCCAGCCCGACTCACACGTGGGTTCCC-3′ (SEQ ID NO: 5135)5′-AGCCCGACUCACACGUGGGUUCCcg-3′ (SEQ ID NO: 1108)3′-GGUCGGGCUGAGUGUGCACCCAAGGGC-5′ (SEQ ID NO: 3122) LDHA-101 Target:5′-CCAGCCCGACTCACACGTGGGTTCCCG-3′ (SEQ ID NO: 5136)5′-GCCCGACUCACACGUGGGUUCCCgc-3′ (SEQ ID NO: 1109)3′-GUCGGGCUGAGUGUGCACCCAAGGGCG-5′ (SEQ ID NO: 3123) LDHA-102 Target:5′-CAGCCCGACTCACACGTGGGTTCCCGC-3′ (SEQ ID NO: 5137)5′-CCCGACUCACACGUGGGUUCCCGca-3′ (SEQ ID NO: 1110)3′-UCGGGCUGAGUGUGCACCCAAGGGCGU-5′ (SEQ ID NO: 3124) LDHA-103 Target:5′-AGCCCGACTCACACGTGGGTTCCCGCA-3′ (SEQ ID NO: 5138)5′-CCGACUCACACGUGGGUUCCCGCac-3′ (SEQ ID NO: 1111)3′-CGGGCUGAGUGUGCACCCAAGGGCGUG-5′ (SEQ ID NO: 3125) LDHA-104 Target:5′-GCCCGACTCACACGTGGGTTCCCGCAC-3′ (SEQ ID NO: 5139)5′-CGACUCACACGUGGGUUCCCGCAcg-3′ (SEQ ID NO: 1112)3′-GGGCUGAGUGUGCACCCAAGGGCGUGC-5′ (SEQ ID NO: 3126) LDHA-105 Target:5′-CCCGACTCACACGTGGGTTCCCGCACG-3′ (SEQ ID NO: 5140)5′-GACUCACACGUGGGUUCCCGCACgt-3′ (SEQ ID NO: 1113)3′-GGCUGAGUGUGCACCCAAGGGCGUGCA-5′ (SEQ ID NO: 3127) LDHA-106 Target:5′-CCGACTCACACGTGGGTTCCCGCACGT-3′ (SEQ ID NO: 5141)5′-ACUCACACGUGGGUUCCCGCACGtc-3′ (SEQ ID NO: 1114)3′-GCUGAGUGUGCACCCAAGGGCGUGCAG-5′ (SEQ ID NO: 3128) LDHA-107 Target:5′-CGACTCACACGTGGGTTCCCGCACGTC-3′ (SEQ ID NO: 5142)5′-CUCACACGUGGGUUCCCGCACGUcc-3′ (SEQ ID NO: 1115)3′-CUGAGUGUGCACCCAAGGGCGUGCAGG-5′ (SEQ ID NO: 3129) LDHA-108 Target:5′-GACTCACACGTGGGTTCCCGCACGTCC-3′ (SEQ ID NO: 5143)5′-UCACACGUGGGUUCCCGCACGUCcg-3′ (SEQ ID NO: 1116)3′-UGAGUGUGCACCCAAGGGCGUGCAGGC-5′ (SEQ ID NO: 3130) LDHA-109 Target:5′-ACTCACACGTGGGTTCCCGCACGTCCG-3′ (SEQ ID NO: 5144)5′-CACACGUGGGUUCCCGCACGUCCgc-3′ (SEQ ID NO: 1117)3′-GAGUGUGCACCCAAGGGCGUGCAGGCG-5′ (SEQ ID NO: 3131) LDHA-110 Target:5′-CTCACACGTGGGTTCCCGCACGTCCGC-3′ (SEQ ID NO: 5145)5′-ACACGUGGGUUCCCGCACGUCCGcc-3′ (SEQ ID NO: 1118)3′-AGUGUGCACCCAAGGGCGUGCAGGCGG-5′ (SEQ ID NO: 3132) LDHA-111 Target:5′-TCACACGTGGGTTCCCGCACGTCCGCC-3′ (SEQ ID NO: 5146)5′-CACGUGGGUUCCCGCACGUCCGCcg-3′ (SEQ ID NO: 1119)3′-GUGUGCACCCAAGGGCGUGCAGGCGGC-5′ (SEQ ID NO: 3133) LDHA-112 Target:5′-CACACGTGGGTTCCCGCACGTCCGCCG-3′ (SEQ ID NO: 5147)5′-CGGCCCCCCCCGCUGACGUCAGCat-3′ (SEQ ID NO: 1120)3′-CGGCCGGGGGGGGCGACUGCAGUCGUA-5′ (SEQ ID NO: 3134) LDHA-135 Target:5′-GCCGGCCCCCCCCGCTGACGTCAGCAT-3′ (SEQ ID NO: 5148)5′-GGCCCCCCCCGCUGACGUCAGCAta-3′ (SEQ ID NO: 1121)3′-GGCCGGGGGGGGCGACUGCAGUCGUAU-5′ (SEQ ID NO: 3135) LDHA-136 Target:5′-CCGGCCCCCCCCGCTGACGTCAGCATA-3′ (SEQ ID NO: 5149)5′-GCCCCCCCCGCUGACGUCAGCAUag-3′ (SEQ ID NO: 1122)3′-GCCGGGGGGGGCGACUGCAGUCGUAUC-5′ (SEQ ID NO: 3136) LDHA-137 Target:5′-CGGCCCCCCCCGCTGACGTCAGCATAG-3′ (SEQ ID NO: 5150)5′-CCCCCCCCGCUGACGUCAGCAUAgc-3′ (SEQ ID NO: 1123)3′-CCGGGGGGGGCGACUGCAGUCGUAUCG-5′ (SEQ ID NO: 3137) LDHA-138 Target:5′-GGCCCCCCCCGCTGACGTCAGCATAGC-3′ (SEQ ID NO: 5151)5′-CCCCCCCGCUGACGUCAGCAUAGct-3′ (SEQ ID NO: 1124)3′-CGGGGGGGGCGACUGCAGUCGUAUCGA-5′ (SEQ ID NO: 3138) LDHA-139 Target:5′-GCCCCCCCCGCTGACGTCAGCATAGCT-3′ (SEQ ID NO: 5152)5′-CCCCCCGCUGACGUCAGCAUAGCtg-3′ (SEQ ID NO: 1125)3′-GGGGGGGGCGACUGCAGUCGUAUCGAC-5′ (SEQ ID NO: 3139) LDHA-140 Target:5′-CCCCCCCCGCTGACGTCAGCATAGCTG-3′ (SEQ ID NO: 5153)5′-CCCCCGCUGACGUCAGCAUAGCUgt-3′ (SEQ ID NO: 1126)3′-GGGGGGGCGACUGCAGUCGUAUCGACA-5′ (SEQ ID NO: 3140) LDHA-141 Target:5′-CCCCCCCGCTGACGTCAGCATAGCTGT-3′ (SEQ ID NO: 5154)5′-CCCCGCUGACGUCAGCAUAGCUGtt-3′ (SEQ ID NO: 1127)3′-GGGGGGCGACUGCAGUCGUAUCGACAA-5′ (SEQ ID NO: 3141) LDHA-142 Target:5′-CCCCCCGCTGACGTCAGCATAGCTGTT-3′ (SEQ ID NO: 5155)5′-CCCGCUGACGUCAGCAUAGCUGUtc-3′ (SEQ ID NO: 1128)3′-GGGGGCGACUGCAGUCGUAUCGACAAG-5′ (SEQ ID NO: 3142) LDHA-143 Target:5′-CCCCCGCTGACGTCAGCATAGCTGTTC-3′ (SEQ ID NO: 5156)5′-CCGCUGACGUCAGCAUAGCUGUUcc-3′ (SEQ ID NO: 1129)3′-GGGGCGACUGCAGUCGUAUCGACAAGG-5′ (SEQ ID NO: 3143) LDHA-144 Target:5′-CCCCGCTGACGTCAGCATAGCTGTTCC-3′ (SEQ ID NO: 5157)5′-CGCUGACGUCAGCAUAGCUGUUCca-3′ (SEQ ID NO: 1130)3′-GGGCGACUGCAGUCGUAUCGACAAGGU-5′ (SEQ ID NO: 3144) LDHA-145 Target:5′-CCCGCTGACGTCAGCATAGCTGTTCCA-3′ (SEQ ID NO: 5158)5′-GCUGACGUCAGCAUAGCUGUUCCac-3′ (SEQ ID NO: 1131)3′-GGCGACUGCAGUCGUAUCGACAAGGUG-5′ (SEQ ID NO: 3145) LDHA-146 Target:5′-CCGCTGACGTCAGCATAGCTGTTCCAC-3′ (SEQ ID NO: 5159)5′-CUGACGUCAGCAUAGCUGUUCCAct-3′ (SEQ ID NO: 1132)3′-GCGACUGCAGUCGUAUCGACAAGGUGA-5′ (SEQ ID NO: 3146) LDHA-147 Target:5′-CGCTGACGTCAGCATAGCTGTTCCACT-3′ (SEQ ID NO: 5160)5′-UGACGUCAGCAUAGCUGUUCCACtt-3′ (SEQ ID NO: 1133)3′-CGACUGCAGUCGUAUCGACAAGGUGAA-5′ (SEQ ID NO: 3147) LDHA-148 Target:5′-GCTGACGTCAGCATAGCTGTTCCACTT-3′ (SEQ ID NO: 5161)5′-GACGUCAGCAUAGCUGUUCCACUta-3′ (SEQ ID NO: 1134)3′-GACUGCAGUCGUAUCGACAAGGUGAAU-5′ (SEQ ID NO: 3148) LDHA-149 Target:5′-CTGACGTCAGCATAGCTGTTCCACTTA-3′ (SEQ ID NO: 5162)5′-ACGUCAGCAUAGCUGUUCCACUUaa-3′ (SEQ ID NO: 1135)3′-ACUGCAGUCGUAUCGACAAGGUGAAUU-5′ (SEQ ID NO: 3149) LDHA-150 Target:5′-TGACGTCAGCATAGCTGTTCCACTTAA-3′ (SEQ ID NO: 5163)5′-CGUCAGCAUAGCUGUUCCACUUAag-3′ (SEQ ID NO: 1136)3′-CUGCAGUCGUAUCGACAAGGUGAAUUC-5′ (SEQ ID NO: 3150) LDHA-151 Target:5′-GACGTCAGCATAGCTGTTCCACTTAAG-3′ (SEQ ID NO: 5164)5′-GUCAGCAUAGCUGUUCCACUUAAgg-3′ (SEQ ID NO: 1137)3′-UGCAGUCGUAUCGACAAGGUGAAUUCC-5′ (SEQ ID NO: 3151) LDHA-152 Target:5′-ACGTCAGCATAGCTGTTCCACTTAAGG-3′ (SEQ ID NO: 5165)5′-UCAGCAUAGCUGUUCCACUUAAGgc-3′ (SEQ ID NO: 1138)3′-GCAGUCGUAUCGACAAGGUGAAUUCCG-5′ (SEQ ID NO: 3152) LDHA-153 Target:5′-CGTCAGCATAGCTGTTCCACTTAAGGC-3′ (SEQ ID NO: 5166)5′-CAGCAUAGCUGUUCCACUUAAGGcc-3′ (SEQ ID NO: 1139)3′-CAGUCGUAUCGACAAGGUGAAUUCCGG-5′ (SEQ ID NO: 3153) LDHA-154 Target:5′-GTCAGCATAGCTGTTCCACTTAAGGCC-3′ (SEQ ID NO: 5167)5′-AGCAUAGCUGUUCCACUUAAGGCcc-3′ (SEQ ID NO: 1140)3′-AGUCGUAUCGACAAGGUGAAUUCCGGG-5′ (SEQ ID NO: 3154) LDHA-155 Target:5′-TCAGCATAGCTGTTCCACTTAAGGCCC-3′ (SEQ ID NO: 5168)5′-GCAUAGCUGUUCCACUUAAGGCCcc-3′ (SEQ ID NO: 1141)3′-GUCGUAUCGACAAGGUGAAUUCCGGGG-5′ (SEQ ID NO: 3155) LDHA-156 Target:5′-CAGCATAGCTGTTCCACTTAAGGCCCC-3′ (SEQ ID NO: 5169)5′-CAUAGCUGUUCCACUUAAGGCCCct-3′ (SEQ ID NO: 1142)3′-UCGUAUCGACAAGGUGAAUUCCGGGGA-5′ (SEQ ID NO: 3156) LDHA-157 Target:5′-AGCATAGCTGTTCCACTTAAGGCCCCT-3′ (SEQ ID NO: 5170)5′-AUAGCUGUUCCACUUAAGGCCCCtc-3′ (SEQ ID NO: 1143)3′-CGUAUCGACAAGGUGAAUUCCGGGGAG-5′ (SEQ ID NO: 3157) LDHA-158 Target:5′-GCATAGCTGTTCCACTTAAGGCCCCTC-3′ (SEQ ID NO: 5171)5′-UAGCUGUUCCACUUAAGGCCCCUcc-3′ (SEQ ID NO: 1144)3′-GUAUCGACAAGGUGAAUUCCGGGGAGG-5′ (SEQ ID NO: 3158) LDHA-159 Target:5′-CATAGCTGTTCCACTTAAGGCCCCTCC-3′ (SEQ ID NO: 5172)5′-AGCUGUUCCACUUAAGGCCCCUCcc-3′ (SEQ ID NO: 1145)3′-UAUCGACAAGGUGAAUUCCGGGGAGGG-5′ (SEQ ID NO: 3159) LDHA-160 Target:5′-ATAGCTGTTCCACTTAAGGCCCCTCCC-3′ (SEQ ID NO: 5173)5′-GCUGUUCCACUUAAGGCCCCUCCcg-3′ (SEQ ID NO: 1146)3′-AUCGACAAGGUGAAUUCCGGGGAGGGC-5′ (SEQ ID NO: 3160) LDHA-161 Target:5′-TAGCTGTTCCACTTAAGGCCCCTCCCG-3′ (SEQ ID NO: 5174)5′-CUGUUCCACUUAAGGCCCCUCCCgc-3′ (SEQ ID NO: 1147)3′-UCGACAAGGUGAAUUCCGGGGAGGGCG-5′ (SEQ ID NO: 3161) LDHA-162 Target:5′-AGCTGTTCCACTTAAGGCCCCTCCCGC-3′ (SEQ ID NO: 5175)5′-CCUCCCGCGCCCAGCUCAGAGUGct-3′ (SEQ ID NO: 1148)3′-GGGGAGGGCGCGGGUCGAGUCUCACGA-5′ (SEQ ID NO: 3162) LDHA-179 Target:5′-CCCCTCCCGCGCCCAGCTCAGAGTGCT-3′ (SEQ ID NO: 5176)5′-CCCGCGCCCAGCUCAGAGUGCUGca-3′ (SEQ ID NO: 1149)3′-GAGGGCGCGGGUCGAGUCUCACGACGU-5′ (SEQ ID NO: 3163) LDHA-182 Target:5′-CTCCCGCGCCCAGCTCAGAGTGCTGCA-3′ (SEQ ID NO: 5177)5′-CCGCGCCCAGCUCAGAGUGCUGCag-3′ (SEQ ID NO: 1150)3′-AGGGCGCGGGUCGAGUCUCACGACGUC-5′ (SEQ ID NO: 3164) LDHA-183 Target:5′-TCCCGCGCCCAGCTCAGAGTGCTGCAG-3′ (SEQ ID NO: 5178)5′-CGCGCCCAGCUCAGAGUGCUGCAgc-3′ (SEQ ID NO: 1151)3′-GGGCGCGGGUCGAGUCUCACGACGUCG-5′ (SEQ ID NO: 3165) LDHA-184 Target:5′-CCCGCGCCCAGCTCAGAGTGCTGCAGC-3′ (SEQ ID NO: 5179)5′-GCGCCCAGCUCAGAGUGCUGCAGcc-3′ (SEQ ID NO: 1152)3′-GGCGCGGGUCGAGUCUCACGACGUCGG-5′ (SEQ ID NO: 3166) LDHA-185 Target:5′-CCGCGCCCAGCTCAGAGTGCTGCAGCC-3′ (SEQ ID NO: 5180)5′-GCCCAGCUCAGAGUGCUGCAGCCgc-3′ (SEQ ID NO: 1153)3′-CGCGGGUCGAGUCUCACGACGUCGGCG-5′ (SEQ ID NO: 3167) LDHA-187 Target:5′-GCGCCCAGCTCAGAGTGCTGCAGCCGC-3′ (SEQ ID NO: 5181)5′-CCCAGCUCAGAGUGCUGCAGCCGct-3′ (SEQ ID NO: 1154)3′-GCGGGUCGAGUCUCACGACGUCGGCGA-5′ (SEQ ID NO: 3168) LDHA-188 Target:5′-CGCCCAGCTCAGAGTGCTGCAGCCGCT-3′ (SEQ ID NO: 5182)5′-CAGCUCAGAGUGCUGCAGCCGCUgc-3′ (SEQ ID NO: 1155)3′-GGGUCGAGUCUCACGACGUCGGCGACG-5′ (SEQ ID NO: 3169) LDHA-190 Target:5′-CCCAGCTCAGAGTGCTGCAGCCGCTGC-3′ (SEQ ID NO: 5183)5′-AGCUCAGAGUGCUGCAGCCGCUGcc-3′ (SEQ ID NO: 1156)3′-GGUCGAGUCUCACGACGUCGGCGACGG-5′ (SEQ ID NO: 3170) LDHA-191 Target:5′-CCAGCTCAGAGTGCTGCAGCCGCTGCC-3′ (SEQ ID NO: 5184)5′-GCUCAGAGUGCUGCAGCCGCUGCcg-3′ (SEQ ID NO: 1157)3′-GUCGAGUCUCACGACGUCGGCGACGGC-5′ (SEQ ID NO: 3171) LDHA-192 Target:5′-CAGCTCAGAGTGCTGCAGCCGCTGCCG-3′ (SEQ ID NO: 5185)5′-CUCAGAGUGCUGCAGCCGCUGCCgc-3′ (SEQ ID NO: 1158)3′-UCGAGUCUCACGACGUCGGCGACGGCG-5′ (SEQ ID NO: 3172) LDHA-193 Target:5′-AGCTCAGAGTGCTGCAGCCGCTGCCGC-3′ (SEQ ID NO: 5186)5′-CCGCUGCCGCCGAUUCCGGAUCUca-3′ (SEQ ID NO: 1159)3′-UCGGCGACGGCGGCUAAGGCCUAGAGU-5′ (SEQ ID NO: 3173) LDHA-208 Target:5′-AGCCGCTGCCGCCGATTCCGGATCTCA-3′ (SEQ ID NO: 5187)5′-CGCUGCCGCCGAUUCCGGAUCUCat-3′ (SEQ ID NO: 1160)3′-CGGCGACGGCGGCUAAGGCCUAGAGUA-5′ (SEQ ID NO: 3174) LDHA-209 Target:5′-GCCGCTGCCGCCGATTCCGGATCTCAT-3′ (SEQ ID NO: 5188)5′-GCUGCCGCCGAUUCCGGAUCUCAtt-3′ (SEQ ID NO: 1161)3′-GGCGACGGCGGCUAAGGCCUAGAGUAA-5′ (SEQ ID NO: 3175) LDHA-210 Target:5′-CCGCTGCCGCCGATTCCGGATCTCATT-3′ (SEQ ID NO: 5189)5′-CUGCCGCCGAUUCCGGAUCUCAUtg-3′ (SEQ ID NO: 1162)3′-GCGACGGCGGCUAAGGCCUAGAGUAAC-5′ (SEQ ID NO: 3176) LDHA-211 Target:5′-CGCTGCCGCCGATTCCGGATCTCATTG-3′ (SEQ ID NO: 5190)5′-UGCCGCCGAUUCCGGAUCUCAUUgc-3′ (SEQ ID NO: 1163)3′-CGACGGCGGCUAAGGCCUAGAGUAACG-5′ (SEQ ID NO: 3177) LDHA-212 Target:5′-GCTGCCGCCGATTCCGGATCTCATTGC-3′ (SEQ ID NO: 5191)5′-GCCGCCGAUUCCGGAUCUCAUUGcc-3′ (SEQ ID NO: 1164)3′-GACGGCGGCUAAGGCCUAGAGUAACGG-5′ (SEQ ID NO: 3178) LDHA-213 Target:5′-CTGCCGCCGATTCCGGATCTCATTGCC-3′ (SEQ ID NO: 5192)5′-CCGCCGAUUCCGGAUCUCAUUGCca-3′ (SEQ ID NO: 1165)3′-ACGGCGGCUAAGGCCUAGAGUAACGGU-5′ (SEQ ID NO: 3179) LDHA-214 Target:5′-TGCCGCCGATTCCGGATCTCATTGCCA-3′ (SEQ ID NO: 5193)5′-CGCCGAUUCCGGAUCUCAUUGCCac-3′ (SEQ ID NO: 1166)3′-CGGCGGCUAAGGCCUAGAGUAACGGUG-5′ (SEQ ID NO: 3180) LDHA-215 Target:5′-GCCGCCGATTCCGGATCTCATTGCCAC-3′ (SEQ ID NO: 5194)5′-GCCGAUUCCGGAUCUCAUUGCCAcg-3′ (SEQ ID NO: 1167)3′-GGCGGCUAAGGCCUAGAGUAACGGUGC-5′ (SEQ ID NO: 3181) LDHA-216 Target:5′-CCGCCGATTCCGGATCTCATTGCCACG-3′ (SEQ ID NO: 5195)5′-CCGAUUCCGGAUCUCAUUGCCACgc-3′ (SEQ ID NO: 1168)3′-GCGGCUAAGGCCUAGAGUAACGGUGCG-5′ (SEQ ID NO: 3182) LDHA-217 Target:5′-CGCCGATTCCGGATCTCATTGCCACGC-3′ (SEQ ID NO: 5196)5′-CGAUUCCGGAUCUCAUUGCCACGcg-3′ (SEQ ID NO: 1169)3′-CGGCUAAGGCCUAGAGUAACGGUGCGC-5′ (SEQ ID NO: 3183) LDHA-218 Target:5′-GCCGATTCCGGATCTCATTGCCACGCG-3′ (SEQ ID NO: 5197)5′-GAUUCCGGAUCUCAUUGCCACGCgc-3′ (SEQ ID NO: 1170)3′-GGCUAAGGCCUAGAGUAACGGUGCGCG-5′ (SEQ ID NO: 3184) LDHA-219 Target:5′-CCGATTCCGGATCTCATTGCCACGCGC-3′ (SEQ ID NO: 5198)5′-AUUCCGGAUCUCAUUGCCACGCGcc-3′ (SEQ ID NO: 1171)3′-GCUAAGGCCUAGAGUAACGGUGCGCGG-5′ (SEQ ID NO: 3185) LDHA-220 Target:5′-CGATTCCGGATCTCATTGCCACGCGCC-3′ (SEQ ID NO: 5199)5′-UUCCGGAUCUCAUUGCCACGCGCcc-3′ (SEQ ID NO: 1172)3′-CUAAGGCCUAGAGUAACGGUGCGCGGG-5′ (SEQ ID NO: 3186) LDHA-221 Target:5′-GATTCCGGATCTCATTGCCACGCGCCC-3′ (SEQ ID NO: 5200)5′-UCCGGAUCUCAUUGCCACGCGCCcc-3′ (SEQ ID NO: 1173)3′-UAAGGCCUAGAGUAACGGUGCGCGGGG-5′ (SEQ ID NO: 3187) LDHA-222 Target:5′-ATTCCGGATCTCATTGCCACGCGCCCC-3′ (SEQ ID NO: 5201)5′-CCGGAUCUCAUUGCCACGCGCCCcc-3′ (SEQ ID NO: 1174)3′-AAGGCCUAGAGUAACGGUGCGCGGGGG-5′ (SEQ ID NO: 3188) LDHA-223 Target:5′-TTCCGGATCTCATTGCCACGCGCCCCC-3′ (SEQ ID NO: 5202)5′-CGGAUCUCAUUGCCACGCGCCCCcg-3′ (SEQ ID NO: 1175)3′-AGGCCUAGAGUAACGGUGCGCGGGGGC-5′ (SEQ ID NO: 3189) LDHA-224 Target:5′-TCCGGATCTCATTGCCACGCGCCCCCG-3′ (SEQ ID NO: 5203)5′-GGAUCUCAUUGCCACGCGCCCCCga-3′ (SEQ ID NO: 1176)3′-GGCCUAGAGUAACGGUGCGCGGGGGCU-5′ (SEQ ID NO: 3190) LDHA-225 Target:5′-CCGGATCTCATTGCCACGCGCCCCCGA-3′ (SEQ ID NO: 5204)5′-GAUCUCAUUGCCACGCGCCCCCGac-3′ (SEQ ID NO: 1177)3′-GCCUAGAGUAACGGUGCGCGGGGGCUG-5′ (SEQ ID NO: 3191) LDHA-226 Target:5′-CGGATCTCATTGCCACGCGCCCCCGAC-3′ (SEQ ID NO: 5205)5′-AUCUCAUUGCCACGCGCCCCCGAcg-3′ (SEQ ID NO: 1178)3′-CCUAGAGUAACGGUGCGCGGGGGCUGC-5′ (SEQ ID NO: 3192) LDHA-227 Target:5′-GGATCTCATTGCCACGCGCCCCCGACG-3′ (SEQ ID NO: 5206)5′-UCUCAUUGCCACGCGCCCCCGACga-3′ (SEQ ID NO: 1179)3′-CUAGAGUAACGGUGCGCGGGGGCUGCU-5′ (SEQ ID NO: 3193) LDHA-228 Target:5′-GATCTCATTGCCACGCGCCCCCGACGA-3′ (SEQ ID NO: 5207)5′-CUCAUUGCCACGCGCCCCCGACGac-3′ (SEQ ID NO: 1180)3′-UAGAGUAACGGUGCGCGGGGGCUGCUG-5′ (SEQ ID NO: 3194) LDHA-229 Target:5′-ATCTCATTGCCACGCGCCCCCGACGAC-3′ (SEQ ID NO: 5208)5′-UCAUUGCCACGCGCCCCCGACGAcc-3′ (SEQ ID NO: 1181)3′-AGAGUAACGGUGCGCGGGGGCUGCUGG-5′ (SEQ ID NO: 3195) LDHA-230 Target:5′-TCTCATTGCCACGCGCCCCCGACGACC-3′ (SEQ ID NO: 5209)5′-CAUUGCCACGCGCCCCCGACGACcg-3′ (SEQ ID NO: 1182)3′-GAGUAACGGUGCGCGGGGGCUGCUGGC-5′ (SEQ ID NO: 3196) LDHA-231 Target:5′-CTCATTGCCACGCGCCCCCGACGACCG-3′ (SEQ ID NO: 5210)5′-AUUGCCACGCGCCCCCGACGACCgc-3′ (SEQ ID NO: 1183)3′-AGUAACGGUGCGCGGGGGCUGCUGGCG-5′ (SEQ ID NO: 3197) LDHA-232 Target:5′-TCATTGCCACGCGCCCCCGACGACCGC-3′ (SEQ ID NO: 5211)5′-CCCCGACGACCGCCCGACGUGCAtt-3′ (SEQ ID NO: 1184)3′-CGGGGGCUGCUGGCGGGCUGCACGUAA-5′ (SEQ ID NO: 3198) LDHA-244 Target:5′-GCCCCCGACGACCGCCCGACGTGCATT-3′ (SEQ ID NO: 5212)5′-CCCGACGACCGCCCGACGUGCAUtc-3′ (SEQ ID NO: 1185)3′-GGGGGCUGCUGGCGGGCUGCACGUAAG-5′ (SEQ ID NO: 3199) LDHA-245 Target:5′-CCCCCGACGACCGCCCGACGTGCATTC-3′ (SEQ ID NO: 5213)5′-CCGACGACCGCCCGACGUGCAUUcc-3′ (SEQ ID NO: 1186)3′-GGGGCUGCUGGCGGGCUGCACGUAAGG-5′ (SEQ ID NO: 3200) LDHA-246 Target:5′-CCCCGACGACCGCCCGACGTGCATTCC-3′ (SEQ ID NO: 5214)5′-CGACGACCGCCCGACGUGCAUUCcc-3′ (SEQ ID NO: 1187)3′-GGGCUGCUGGCGGGCUGCACGUAAGGG-5′ (SEQ ID NO: 3201) LDHA-247 Target:5′-CCCGACGACCGCCCGACGTGCATTCCC-3′ (SEQ ID NO: 5215)5′-GACGACCGCCCGACGUGCAUUCCcg-3′ (SEQ ID NO: 1188)3′-GGCUGCUGGCGGGCUGCACGUAAGGGC-5′ (SEQ ID NO: 3202) LDHA-248 Target:5′-CCGACGACCGCCCGACGTGCATTCCCG-3′ (SEQ ID NO: 5216)5′-ACGACCGCCCGACGUGCAUUCCCga-3′ (SEQ ID NO: 1189)3′-GCUGCUGGCGGGCUGCACGUAAGGGCU-5′ (SEQ ID NO: 3203) LDHA-249 Target:5′-CGACGACCGCCCGACGTGCATTCCCGA-3′ (SEQ ID NO: 5217)5′-CGACCGCCCGACGUGCAUUCCCGat-3′ (SEQ ID NO: 1190)3′-CUGCUGGCGGGCUGCACGUAAGGGCUA-5′ (SEQ ID NO: 3204) LDHA-250 Target:5′-GACGACCGCCCGACGTGCATTCCCGAT-3′ (SEQ ID NO: 5218)5′-GACCGCCCGACGUGCAUUCCCGAtt-3′ (SEQ ID NO: 1191)3′-UGCUGGCGGGCUGCACGUAAGGGCUAA-5′ (SEQ ID NO: 3205) LDHA-251 Target:5′-ACGACCGCCCGACGTGCATTCCCGATT-3′ (SEQ ID NO: 5219)5′-ACCGCCCGACGUGCAUUCCCGAUtc-3′ (SEQ ID NO: 1192)3′-GCUGGCGGGCUGCACGUAAGGGCUAAG-5′ (SEQ ID NO: 3206) LDHA-252 Target:5′-CGACCGCCCGACGTGCATTCCCGATTC-3′ (SEQ ID NO: 5220)5′-CCGCCCGACGUGCAUUCCCGAUUcc-3′ (SEQ ID NO: 1193)3′-CUGGCGGGCUGCACGUAAGGGCUAAGG-5′ (SEQ ID NO: 3207) LDHA-253 Target:5′-GACCGCCCGACGTGCATTCCCGATTCC-3′ (SEQ ID NO: 5221)5′-CGCCCGACGUGCAUUCCCGAUUCct-3′ (SEQ ID NO: 1194)3′-UGGCGGGCUGCACGUAAGGGCUAAGGA-5′ (SEQ ID NO: 3208) LDHA-254 Target:5′-ACCGCCCGACGTGCATTCCCGATTCCT-3′ (SEQ ID NO: 5222)5′-GCCCGACGUGCAUUCCCGAUUCCtt-3′ (SEQ ID NO: 1195)3′-GGCGGGCUGCACGUAAGGGCUAAGGAA-5′ (SEQ ID NO: 3209) LDHA-255 Target:5′-CCGCCCGACGTGCATTCCCGATTCCTT-3′ (SEQ ID NO: 5223)5′-CCCGACGUGCAUUCCCGAUUCCUtt-3′ (SEQ ID NO: 1196)3′-GCGGGCUGCACGUAAGGGCUAAGGAAA-5′ (SEQ ID NO: 3210) LDHA-256 Target:5′-CGCCCGACGTGCATTCCCGATTCCTTT-3′ (SEQ ID NO: 5224)5′-CCGACGUGCAUUCCCGAUUCCUUtt-3′ (SEQ ID NO: 1197)3′-CGGGCUGCACGUAAGGGCUAAGGAAAA-5′ (SEQ ID NO: 3211) LDHA-257 Target:5′-GCCCGACGTGCATTCCCGATTCCTTTT-3′ (SEQ ID NO: 5225)5′-CGACGUGCAUUCCCGAUUCCUUUtg-3′ (SEQ ID NO: 1198)3′-GGGCUGCACGUAAGGGCUAAGGAAAAC-5′ (SEQ ID NO: 3212) LDHA-258 Target:5′-CCCGACGTGCATTCCCGATTCCTTTTG-3′ (SEQ ID NO: 5226)5′-GACGUGCAUUCCCGAUUCCUUUUgg-3′ (SEQ ID NO: 1199)3′-GGCUGCACGUAAGGGCUAAGGAAAACC-5′ (SEQ ID NO: 3213) LDHA-259 Target:5′-CCGACGTGCATTCCCGATTCCTTTTGG-3′ (SEQ ID NO: 5227)5′-ACGUGCAUUCCCGAUUCCUUUUGgt-3′ (SEQ ID NO: 1200)3′-GCUGCACGUAAGGGCUAAGGAAAACCA-5′ (SEQ ID NO: 3214) LDHA-260 Target:5′-CGACGTGCATTCCCGATTCCTTTTGGT-3′ (SEQ ID NO: 5228)5′-CGUGCAUUCCCGAUUCCUUUUGGtt-3′ (SEQ ID NO: 1201)3′-CUGCACGUAAGGGCUAAGGAAAACCAA-5′ (SEQ ID NO: 3215) LDHA-261 Target:5′-GACGTGCATTCCCGATTCCTTTTGGTT-3′ (SEQ ID NO: 5229)5′-GUGCAUUCCCGAUUCCUUUUGGUtc-3′ (SEQ ID NO: 1202)3′-UGCACGUAAGGGCUAAGGAAAACCAAG-5′ (SEQ ID NO: 3216) LDHA-262 Target:5′-ACGTGCATTCCCGATTCCTTTTGGTTC-3′ (SEQ ID NO: 5230)5′-UGCAUUCCCGAUUCCUUUUGGUUcc-3′ (SEQ ID NO: 1203)3′-GCACGUAAGGGCUAAGGAAAACCAAGG-5′ (SEQ ID NO: 3217) LDHA-263 Target:5′-CGTGCATTCCCGATTCCTTTTGGTTCC-3′ (SEQ ID NO: 5231)5′-GCAUUCCCGAUUCCUUUUGGUUCca-3′ (SEQ ID NO: 1204)3′-CACGUAAGGGCUAAGGAAAACCAAGGU-5′ (SEQ ID NO: 3218) LDHA-264 Target:5′-GTGCATTCCCGATTCCTTTTGGTTCCA-3′ (SEQ ID NO: 5232)5′-CAUUCCCGAUUCCUUUUGGUUCCaa-3′ (SEQ ID NO: 1205)3′-ACGUAAGGGCUAAGGAAAACCAAGGUU-5′ (SEQ ID NO: 3219) LDHA-265 Target:5′-TGCATTCCCGATTCCTTTTGGTTCCAA-3′ (SEQ ID NO: 5233)5′-AUUCCCGAUUCCUUUUGGUUCCAag-3′ (SEQ ID NO: 1206)3′-CGUAAGGGCUAAGGAAAACCAAGGUUC-5′ (SEQ ID NO: 3220) LDHA-266 Target:5′-GCATTCCCGATTCCTTTTGGTTCCAAG-3′ (SEQ ID NO: 5234)5′-UUCCCGAUUCCUUUUGGUUCCAAgt-3′ (SEQ ID NO: 1207)3′-GUAAGGGCUAAGGAAAACCAAGGUUCA-5′ (SEQ ID NO: 3221) LDHA-267 Target:5′-CATTCCCGATTCCTTTTGGTTCCAAGT-3′ (SEQ ID NO: 5235)5′-UCCCGAUUCCUUUUGGUUCCAAGtc-3′ (SEQ ID NO: 1208)3′-UAAGGGCUAAGGAAAACCAAGGUUCAG-5′ (SEQ ID NO: 3222) LDHA-268 Target:5′-ATTCCCGATTCCTTTTGGTTCCAAGTC-3′ (SEQ ID NO: 5236)5′-CCCGAUUCCUUUUGGUUCCAAGUcc-3′ (SEQ ID NO: 1209)3′-AAGGGCUAAGGAAAACCAAGGUUCAGG-5′ (SEQ ID NO: 3223) LDHA-269 Target:5′-TTCCCGATTCCTTTTGGTTCCAAGTCC-3′ (SEQ ID NO: 5237)5′-CCGAUUCCUUUUGGUUCCAAGUCca-3′ (SEQ ID NO: 1210)3′-AGGGCUAAGGAAAACCAAGGUUCAGGU-5′ (SEQ ID NO: 3224) LDHA-270 Target:5′-TCCCGATTCCTTTTGGTTCCAAGTCCA-3′ (SEQ ID NO: 5238)5′-CGAUUCCUUUUGGUUCCAAGUCCaa-3′ (SEQ ID NO: 1211)3′-GGGCUAAGGAAAACCAAGGUUCAGGUU-5′ (SEQ ID NO: 3225) LDHA-271 Target:5′-CCCGATTCCTTTTGGTTCCAAGTCCAA-3′ (SEQ ID NO: 5239)5′-GAUUCCUUUUGGUUCCAAGUCCAat-3′ (SEQ ID NO: 1212)3′-GGCUAAGGAAAACCAAGGUUCAGGUUA-5′ (SEQ ID NO: 3226) LDHA-272 Target:5′-CCGATTCCTTTTGGTTCCAAGTCCAAT-3′ (SEQ ID NO: 5240)5′-AUUCCUUUUGGUUCCAAGUCCAAta-3′ (SEQ ID NO: 1213)3′-GCUAAGGAAAACCAAGGUUCAGGUUAU-5′ (SEQ ID NO: 3227) LDHA-273 Target:5′-CGATTCCTTTTGGTTCCAAGTCCAATA-3′ (SEQ ID NO: 5241)5′-UUCCUUUUGGUUCCAAGUCCAAUat-3′ (SEQ ID NO: 1214)3′-CUAAGGAAAACCAAGGUUCAGGUUAUA-5′ (SEQ ID NO: 3228) LDHA-274 Target:5′-GATTCCTTTTGGTTCCAAGTCCAATAT-3′ (SEQ ID NO: 5242)5′-UCCUUUUGGUUCCAAGUCCAAUAtg-3′ (SEQ ID NO: 1215)3′-UAAGGAAAACCAAGGUUCAGGUUAUAC-5′ (SEQ ID NO: 3229) LDHA-275 Target:5′-ATTCCTTTTGGTTCCAAGTCCAATATG-3′ (SEQ ID NO: 5243)5′-CCUUUUGGUUCCAAGUCCAAUAUgg-3′ (SEQ ID NO: 1216)3′-AAGGAAAACCAAGGUUCAGGUUAUACC-5′ (SEQ ID NO: 3230) LDHA-276 Target:5′-TTCCTTTTGGTTCCAAGTCCAATATGG-3′ (SEQ ID NO: 5244)5′-CUUUUGGUUCCAAGUCCAAUAUGgc-3′ (SEQ ID NO: 1217)3′-AGGAAAACCAAGGUUCAGGUUAUACCG-5′ (SEQ ID NO: 3231) LDHA-277 Target:5′-TCCTTTTGGTTCCAAGTCCAATATGGC-3′ (SEQ ID NO: 5245)5′-UUUUGGUUCCAAGUCCAAUAUGGca-3′ (SEQ ID NO: 1218)3′-GGAAAACCAAGGUUCAGGUUAUACCGU-5′ (SEQ ID NO: 3232) LDHA-278 Target:5′-CCTTTTGGTTCCAAGTCCAATATGGCA-3′ (SEQ ID NO: 5246)5′-UUUGGUUCCAAGUCCAAUAUGGCaa-3′ (SEQ ID NO: 1219)3′-GAAAACCAAGGUUCAGGUUAUACCGUU-5′ (SEQ ID NO: 3233) LDHA-279 Target:5′-CTTTTGGTTCCAAGTCCAATATGGCAA-3′ (SEQ ID NO: 5247)5′-UUGGUUCCAAGUCCAAUAUGGCAac-3′ (SEQ ID NO: 1220)3′-AAAACCAAGGUUCAGGUUAUACCGUUG-5′ (SEQ ID NO: 3234) LDHA-280 Target:5′-TTTTGGTTCCAAGTCCAATATGGCAAC-3′ (SEQ ID NO: 5248)5′-UGGUUCCAAGUCCAAUAUGGCAAct-3′ (SEQ ID NO: 1221)3′-AAACCAAGGUUCAGGUUAUACCGUUGA-5′ (SEQ ID NO: 3235) LDHA-281 Target:5′-TTTGGTTCCAAGTCCAATATGGCAACT-3′ (SEQ ID NO: 5249)5′-GGUUCCAAGUCCAAUAUGGCAACtc-3′ (SEQ ID NO: 1222)3′-AACCAAGGUUCAGGUUAUACCGUUGAG-5′ (SEQ ID NO: 3236) LDHA-282 Target:5′-TTGGTTCCAAGTCCAATATGGCAACTC-3′ (SEQ ID NO: 5250)5′-GUUCCAAGUCCAAUAUGGCAACUct-3′ (SEQ ID NO: 1223)3′-ACCAAGGUUCAGGUUAUACCGUUGAGA-5′ (SEQ ID NO: 3237) LDHA-283 Target:5′-TGGTTCCAAGTCCAATATGGCAACTCT-3′ (SEQ ID NO: 5251)5′-UUCCAAGUCCAAUAUGGCAACUCta-3′ (SEQ ID NO: 1224)3′-CCAAGGUUCAGGUUAUACCGUUGAGAU-5′ (SEQ ID NO: 3238) LDHA-284 Target:5′-GGTTCCAAGTCCAATATGGCAACTCTA-3′ (SEQ ID NO: 5252)5′-UCCAAGUCCAAUAUGGCAACUCUaa-3′ (SEQ ID NO: 1225)3′-CAAGGUUCAGGUUAUACCGUUGAGAUU-5′ (SEQ ID NO: 3239) LDHA-285 Target:5′-GTTCCAAGTCCAATATGGCAACTCTAA-3′ (SEQ ID NO: 5253)5′-CCAAGUCCAAUAUGGCAACUCUAaa-3′ (SEQ ID NO: 1226)3′-AAGGUUCAGGUUAUACCGUUGAGAUUU-5′ (SEQ ID NO: 3240) LDHA-286 Target:5′-TTCCAAGTCCAATATGGCAACTCTAAA-3′ (SEQ ID NO: 5254)5′-CAAGUCCAAUAUGGCAACUCUAAag-3′ (SEQ ID NO: 1227)3′-AGGUUCAGGUUAUACCGUUGAGAUUUC-5′ (SEQ ID NO: 3241) LDHA-287 Target:5′-TCCAAGTCCAATATGGCAACTCTAAAG-3′ (SEQ ID NO: 5255)5′-AAGUCCAAUAUGGCAACUCUAAAgg-3′ (SEQ ID NO: 1228)3′-GGUUCAGGUUAUACCGUUGAGAUUUCC-5′ (SEQ ID NO: 3242) LDHA-288 Target:5′-CCAAGTCCAATATGGCAACTCTAAAGG-3′ (SEQ ID NO: 5256)5′-AGUCCAAUAUGGCAACUCUAAAGga-3′ (SEQ ID NO: 1229)3′-GUUCAGGUUAUACCGUUGAGAUUUCCU-5′ (SEQ ID NO: 3243) LDHA-289 Target:5′-CAAGTCCAATATGGCAACTCTAAAGGA-3′ (SEQ ID NO: 5257)5′-GUCCAAUAUGGCAACUCUAAAGGat-3′ (SEQ ID NO: 1230)3′-UUCAGGUUAUACCGUUGAGAUUUCCUA-5′ (SEQ ID NO: 3244) LDHA-290 Target:5′-AAGTCCAATATGGCAACTCTAAAGGAT-3′ (SEQ ID NO: 5258)5′-UCCAAUAUGGCAACUCUAAAGGAtc-3′ (SEQ ID NO: 1231)3′-UCAGGUUAUACCGUUGAGAUUUCCUAG-5′ (SEQ ID NO: 3245) LDHA-291 Target:5′-AGTCCAATATGGCAACTCTAAAGGATC-3′ (SEQ ID NO: 5259)5′-CCAAUAUGGCAACUCUAAAGGAUca-3′ (SEQ ID NO: 1232)3′-CAGGUUAUACCGUUGAGAUUUCCUAGU-5′ (SEQ ID NO: 3246) LDHA-292 Target:5′-GTCCAATATGGCAACTCTAAAGGATCA-3′ (SEQ ID NO: 5260)5′-CAAUAUGGCAACUCUAAAGGAUCag-3′ (SEQ ID NO: 1233)3′-AGGUUAUACCGUUGAGAUUUCCUAGUC-5′ (SEQ ID NO: 3247) LDHA-293 Target:5′-TCCAATATGGCAACTCTAAAGGATCAG-3′ (SEQ ID NO: 5261)5′-AAUAUGGCAACUCUAAAGGAUCAgc-3′ (SEQ ID NO: 1234)3′-GGUUAUACCGUUGAGAUUUCCUAGUCG-5′ (SEQ ID NO: 3248) LDHA-294 Target:5′-CCAATATGGCAACTCTAAAGGATCAGC-3′ (SEQ ID NO: 5262)5′-AUAUGGCAACUCUAAAGGAUCAGct-3′ (SEQ ID NO: 1235)3′-GUUAUACCGUUGAGAUUUCCUAGUCGA-5′ (SEQ ID NO: 3249) LDHA-295 Target:5′-CAATATGGCAACTCTAAAGGATCAGCT-3′ (SEQ ID NO: 5263)5′-UAUGGCAACUCUAAAGGAUCAGCtg-3′ (SEQ ID NO: 1236)3′-UUAUACCGUUGAGAUUUCCUAGUCGAC-5′ (SEQ ID NO: 3250) LDHA-296 Target:5′-AATATGGCAACTCTAAAGGATCAGCTG-3′ (SEQ ID NO: 5264)5′-AUGGCAACUCUAAAGGAUCAGCUga-3′ (SEQ ID NO: 1237)3′-UAUACCGUUGAGAUUUCCUAGUCGACU-5′ (SEQ ID NO: 3251) LDHA-297 Target:5′-ATATGGCAACTCTAAAGGATCAGCTGA-3′ (SEQ ID NO: 5265)5′-UGGCAACUCUAAAGGAUCAGCUGat-3′ (SEQ ID NO: 1238)3′-AUACCGUUGAGAUUUCCUAGUCGACUA-5′ (SEQ ID NO: 3252) LDHA-298 Target:5′-TATGGCAACTCTAAAGGATCAGCTGAT-3′ (SEQ ID NO: 5266)5′-GGCAACUCUAAAGGAUCAGCUGAtt-3′ (SEQ ID NO: 1239)3′-UACCGUUGAGAUUUCCUAGUCGACUAA-5′ (SEQ ID NO: 3253) LDHA-299 Target:5′-ATGGCAACTCTAAAGGATCAGCTGATT-3′ (SEQ ID NO: 5267)5′-GCAACUCUAAAGGAUCAGCUGAUtt-3′ (SEQ ID NO: 1240)3′-ACCGUUGAGAUUUCCUAGUCGACUAAA-5′ (SEQ ID NO: 3254) LDHA-300 Target:5′-TGGCAACTCTAAAGGATCAGCTGATTT-3′ (SEQ ID NO: 5268)5′-CAACUCUAAAGGAUCAGCUGAUUta-3′ (SEQ ID NO: 1241)3′-CCGUUGAGAUUUCCUAGUCGACUAAAU-5′ (SEQ ID NO: 3255) LDHA-301 Target:5′-GGCAACTCTAAAGGATCAGCTGATTTA-3′ (SEQ ID NO: 5269)5′-AACUCUAAAGGAUCAGCUGAUUUat-3′ (SEQ ID NO: 1242)3′-CGUUGAGAUUUCCUAGUCGACUAAAUA-5′ (SEQ ID NO: 3256) LDHA-302 Target:5′-GCAACTCTAAAGGATCAGCTGATTTAT-3′ (SEQ ID NO: 5270)5′-ACUCUAAAGGAUCAGCUGAUUUAta-3′ (SEQ ID NO: 1243)3′-GUUGAGAUUUCCUAGUCGACUAAAUAU-5′ (SEQ ID NO: 3257) LDHA-303 Target:5′-CAACTCTAAAGGATCAGCTGATTTATA-3′ (SEQ ID NO: 5271)5′-CUCUAAAGGAUCAGCUGAUUUAUaa-3′ (SEQ ID NO: 1244)3′-UUGAGAUUUCCUAGUCGACUAAAUAUU-5′ (SEQ ID NO: 3258) LDHA-304 Target:5′-AACTCTAAAGGATCAGCTGATTTATAA-3′ (SEQ ID NO: 5272)5′-UCUAAAGGAUCAGCUGAUUUAUAat-3′ (SEQ ID NO: 1245)3′-UGAGAUUUCCUAGUCGACUAAAUAUUA-5′ (SEQ ID NO: 3259) LDHA-305 Target:5′-ACTCTAAAGGATCAGCTGATTTATAAT-3′ (SEQ ID NO: 5273)5′-CUAAAGGAUCAGCUGAUUUAUAAtc-3′ (SEQ ID NO: 1246)3′-GAGAUUUCCUAGUCGACUAAAUAUUAG-5′ (SEQ ID NO: 3260) LDHA-306 Target:5′-CTCTAAAGGATCAGCTGATTTATAATC-3′ (SEQ ID NO: 5274)5′-UAAAGGAUCAGCUGAUUUAUAAUct-3′ (SEQ ID NO: 1247)3′-AGAUUUCCUAGUCGACUAAAUAUUAGA-5′ (SEQ ID NO: 3261) LDHA-307 Target:5′-TCTAAAGGATCAGCTGATTTATAATCT-3′ (SEQ ID NO: 5275)5′-AAAGGAUCAGCUGAUUUAUAAUCtt-3′ (SEQ ID NO: 1248)3′-GAUUUCCUAGUCGACUAAAUAUUAGAA-5′ (SEQ ID NO: 3262) LDHA-308 Target:5′-CTAAAGGATCAGCTGATTTATAATCTT-3′ (SEQ ID NO: 5276)5′-AAGGAUCAGCUGAUUUAUAAUCUtc-3′ (SEQ ID NO: 1249)3′-AUUUCCUAGUCGACUAAAUAUUAGAAG-5′ (SEQ ID NO: 3263) LDHA-309 Target:5′-TAAAGGATCAGCTGATTTATAATCTTC-3′ (SEQ ID NO: 5277)5′-AGGAUCAGCUGAUUUAUAAUCUUct-3′ (SEQ ID NO: 1250)3′-UUUCCUAGUCGACUAAAUAUUAGAAGA-5′ (SEQ ID NO: 3264) LDHA-310 Target:5′-AAAGGATCAGCTGATTTATAATCTTCT-3′ (SEQ ID NO: 5278)5′-GGAUCAGCUGAUUUAUAAUCUUCta-3′ (SEQ ID NO: 1251)3′-UUCCUAGUCGACUAAAUAUUAGAAGAU-5′ (SEQ ID NO: 3265) LDHA-311 Target:5′-AAGGATCAGCTGATTTATAATCTTCTA-3′ (SEQ ID NO: 5279)5′-GAUCAGCUGAUUUAUAAUCUUCUaa-3′ (SEQ ID NO: 1252)3′-UCCUAGUCGACUAAAUAUUAGAAGAUU-5′ (SEQ ID NO: 3266) LDHA-312 Target:5′-AGGATCAGCTGATTTATAATCTTCTAA-3′ (SEQ ID NO: 5280)5′-AUCAGCUGAUUUAUAAUCUUCUAaa-3′ (SEQ ID NO: 1253)3′-CCUAGUCGACUAAAUAUUAGAAGAUUU-5′ (SEQ ID NO: 3267) LDHA-313 Target:5′-GGATCAGCTGATTTATAATCTTCTAAA-3′ (SEQ ID NO: 5281)5′-UCAGCUGAUUUAUAAUCUUCUAAag-3′ (SEQ ID NO: 1254)3′-CUAGUCGACUAAAUAUUAGAAGAUUUC-5′ (SEQ ID NO: 3268) LDHA-314 Target:5′-GATCAGCTGATTTATAATCTTCTAAAG-3′ (SEQ ID NO: 5282)5′-CAGCUGAUUUAUAAUCUUCUAAAgg-3′ (SEQ ID NO: 1255)3′-UAGUCGACUAAAUAUUAGAAGAUUUCC-5′ (SEQ ID NO: 3269) LDHA-315 Target:5′-ATCAGCTGATTTATAATCTTCTAAAGG-3′ (SEQ ID NO: 5283)5′-AGCUGAUUUAUAAUCUUCUAAAGga-3′ (SEQ ID NO: 1256)3′-AGUCGACUAAAUAUUAGAAGAUUUCCU-5′ (SEQ ID NO: 3270) LDHA-316 Target:5′-TCAGCTGATTTATAATCTTCTAAAGGA-3′ (SEQ ID NO: 5284)5′-GCUGAUUUAUAAUCUUCUAAAGGaa-3′ (SEQ ID NO: 1257)3′-GUCGACUAAAUAUUAGAAGAUUUCCUU-5′ (SEQ ID NO: 3271) LDHA-317 Target:5′-CAGCTGATTTATAATCTTCTAAAGGAA-3′ (SEQ ID NO: 5285)5′-CUGAUUUAUAAUCUUCUAAAGGAag-3′ (SEQ ID NO: 1258)3′-UCGACUAAAUAUUAGAAGAUUUCCUUC-5′ (SEQ ID NO: 3272) LDHA-318 Target:5′-AGCTGATTTATAATCTTCTAAAGGAAG-3′ (SEQ ID NO: 5286)5′-UGAUUUAUAAUCUUCUAAAGGAAga-3′ (SEQ ID NO: 1259)3′-CGACUAAAUAUUAGAAGAUUUCCUUCU-5′ (SEQ ID NO: 3273) LDHA-319 Target:5′-GCTGATTTATAATCTTCTAAAGGAAGA-3′ (SEQ ID NO: 5287)5′-GAUUUAUAAUCUUCUAAAGGAAGaa-3′ (SEQ ID NO: 1260)3′-GACUAAAUAUUAGAAGAUUUCCUUCUU-5′ (SEQ ID NO: 3274) LDHA-320 Target:5′-CTGATTTATAATCTTCTAAAGGAAGAA-3′ (SEQ ID NO: 5288)5′-AUUUAUAAUCUUCUAAAGGAAGAac-3′ (SEQ ID NO: 1261)3′-ACUAAAUAUUAGAAGAUUUCCUUCUUG-5′ (SEQ ID NO: 3275) LDHA-321 Target:5′-TGATTTATAATCTTCTAAAGGAAGAAC-3′ (SEQ ID NO: 5289)5′-UUUAUAAUCUUCUAAAGGAAGAAca-3′ (SEQ ID NO: 1262)3′-CUAAAUAUUAGAAGAUUUCCUUCUUGU-5′ (SEQ ID NO: 3276) LDHA-322 Target:5′-GATTTATAATCTTCTAAAGGAAGAACA-3′ (SEQ ID NO: 5290)5′-UUAUAAUCUUCUAAAGGAAGAACag-3′ (SEQ ID NO: 1263)3′-UAAAUAUUAGAAGAUUUCCUUCUUGUC-5′ (SEQ ID NO: 3277) LDHA-323 Target:5′-ATTTATAATCTTCTAAAGGAAGAACAG-3′ (SEQ ID NO: 5291)5′-UAUAAUCUUCUAAAGGAAGAACAga-3′ (SEQ ID NO: 1264)3′-AAAUAUUAGAAGAUUUCCUUCUUGUCU-5′ (SEQ ID NO: 3278) LDHA-324 Target:5′-TTTATAATCTTCTAAAGGAAGAACAGA-3′ (SEQ ID NO: 5292)5′-AUAAUCUUCUAAAGGAAGAACAGac-3′ (SEQ ID NO: 1265)3′-AAUAUUAGAAGAUUUCCUUCUUGUCUG-5′ (SEQ ID NO: 3279) LDHA-325 Target:5′-TTATAATCTTCTAAAGGAAGAACAGAC-3′ (SEQ ID NO: 5293)5′-UAAUCUUCUAAAGGAAGAACAGAcc-3′ (SEQ ID NO: 1266)3′-AUAUUAGAAGAUUUCCUUCUUGUCUGG-5′ (SEQ ID NO: 3280) LDHA-326 Target:5′-TATAATCTTCTAAAGGAAGAACAGACC-3′ (SEQ ID NO: 5294)5′-AAUCUUCUAAAGGAAGAACAGACcc-3′ (SEQ ID NO: 1267)3′-UAUUAGAAGAUUUCCUUCUUGUCUGGG-5′ (SEQ ID NO: 3281) LDHA-327 Target:5′-ATAATCTTCTAAAGGAAGAACAGACCC-3′ (SEQ ID NO: 5295)5′-AUCUUCUAAAGGAAGAACAGACCcc-3′ (SEQ ID NO: 1268)3′-AUUAGAAGAUUUCCUUCUUGUCUGGGG-5′ (SEQ ID NO: 3282) LDHA-328 Target:5′-TAATCTTCTAAAGGAAGAACAGACCCC-3′ (SEQ ID NO: 5296)5′-UCUUCUAAAGGAAGAACAGACCCcc-3′ (SEQ ID NO: 1269)3′-UUAGAAGAUUUCCUUCUUGUCUGGGGG-5′ (SEQ ID NO: 3283) LDHA-329 Target:5′-AATCTTCTAAAGGAAGAACAGACCCCC-3′ (SEQ ID NO: 5297)5′-CUUCUAAAGGAAGAACAGACCCCcc-3′ (SEQ ID NO: 1270)3′-UAGAAGAUUUCCUUCUUGUCUGGGGGG-5′ (SEQ ID NO: 3284) LDHA-330 Target:5′-ATCTTCTAAAGGAAGAACAGACCCCCC-3′ (SEQ ID NO: 5298)5′-UUCUAAAGGAAGAACAGACCCCCca-3′ (SEQ ID NO: 1271)3′-AGAAGAUUUCCUUCUUGUCUGGGGGGU-5′ (SEQ ID NO: 3285) LDHA-331 Target:5′-TCTTCTAAAGGAAGAACAGACCCCCCA-3′ (SEQ ID NO: 5299)5′-UCUAAAGGAAGAACAGACCCCCCag-3′ (SEQ ID NO: 1272)3′-GAAGAUUUCCUUCUUGUCUGGGGGGUC-5′ (SEQ ID NO: 3286) LDHA-332 Target:5′-CTTCTAAAGGAAGAACAGACCCCCCAG-3′ (SEQ ID NO: 5300)5′-CUAAAGGAAGAACAGACCCCCCAga-3′ (SEQ ID NO: 1273)3′-AAGAUUUCCUUCUUGUCUGGGGGGUCU-5′ (SEQ ID NO: 3287) LDHA-333 Target:5′-TTCTAAAGGAAGAACAGACCCCCCAGA-3′ (SEQ ID NO: 5301)5′-UAAAGGAAGAACAGACCCCCCAGaa-3′ (SEQ ID NO: 1274)3′-AGAUUUCCUUCUUGUCUGGGGGGUCUU-5′ (SEQ ID NO: 3288) LDHA-334 Target:5′-TCTAAAGGAAGAACAGACCCCCCAGAA-3′ (SEQ ID NO: 5302)5′-AAAGGAAGAACAGACCCCCCAGAat-3′ (SEQ ID NO: 1275)3′-GAUUUCCUUCUUGUCUGGGGGGUCUUA-5′ (SEQ ID NO: 3289) LDHA-335 Target:5′-CTAAAGGAAGAACAGACCCCCCAGAAT-3′ (SEQ ID NO: 5303)5′-AAGGAAGAACAGACCCCCCAGAAta-3′ (SEQ ID NO: 1276)3′-AUUUCCUUCUUGUCUGGGGGGUCUUAU-5′ (SEQ ID NO: 3290) LDHA-336 Target:5′-TAAAGGAAGAACAGACCCCCCAGAATA-3′ (SEQ ID NO: 5304)5′-AGGAAGAACAGACCCCCCAGAAUaa-3′ (SEQ ID NO: 1277)3′-UUUCCUUCUUGUCUGGGGGGUCUUAUU-5′ (SEQ ID NO: 3291) LDHA-337 Target:5′-AAAGGAAGAACAGACCCCCCAGAATAA-3′ (SEQ ID NO: 5305)5′-GGAAGAACAGACCCCCCAGAAUAag-3′ (SEQ ID NO: 1278)3′-UUCCUUCUUGUCUGGGGGGUCUUAUUC-5′ (SEQ ID NO: 3292) LDHA-338 Target:5′-AAGGAAGAACAGACCCCCCAGAATAAG-3′ (SEQ ID NO: 5306)5′-GAAGAACAGACCCCCCAGAAUAAga-3′ (SEQ ID NO: 1279)3′-UCCUUCUUGUCUGGGGGGUCUUAUUCU-5′ (SEQ ID NO: 3293) LDHA-339 Target:5′-AGGAAGAACAGACCCCCCAGAATAAGA-3′ (SEQ ID NO: 5307)5′-AAGAACAGACCCCCCAGAAUAAGat-3′ (SEQ ID NO: 1280)3′-CCUUCUUGUCUGGGGGGUCUUAUUCUA-5′ (SEQ ID NO: 3294) LDHA-340 Target:5′-GGAAGAACAGACCCCCCAGAATAAGAT-3′ (SEQ ID NO: 5308)5′-AGAACAGACCCCCCAGAAUAAGAtt-3′ (SEQ ID NO: 1281)3′-CUUCUUGUCUGGGGGGUCUUAUUCUAA-5′ (SEQ ID NO: 3295) LDHA-341 Target:5′-GAAGAACAGACCCCCCAGAATAAGATT-3′ (SEQ ID NO: 5309)5′-GAACAGACCCCCCAGAAUAAGAUta-3′ (SEQ ID NO: 1282)3′-UUCUUGUCUGGGGGGUCUUAUUCUAAU-5′ (SEQ ID NO: 3296) LDHA-342 Target:5′-AAGAACAGACCCCCCAGAATAAGATTA-3′ (SEQ ID NO: 5310)5′-AACAGACCCCCCAGAAUAAGAUUac-3′ (SEQ ID NO: 1283)3′-UCUUGUCUGGGGGGUCUUAUUCUAAUG-5′ (SEQ ID NO: 3297) LDHA-343 Target:5′-AGAACAGACCCCCCAGAATAAGATTAC-3′ (SEQ ID NO: 5311)5′-ACAGACCCCCCAGAAUAAGAUUAca-3′ (SEQ ID NO: 1284)3′-CUUGUCUGGGGGGUCUUAUUCUAAUGU-5′ (SEQ ID NO: 3298) LDHA-344 Target:5′-GAACAGACCCCCCAGAATAAGATTACA-3′ (SEQ ID NO: 5312)5′-CAGACCCCCCAGAAUAAGAUUACag-3′ (SEQ ID NO: 1285)3′-UUGUCUGGGGGGUCUUAUUCUAAUGUC-5′ (SEQ ID NO: 3299) LDHA-345 Target:5′-AACAGACCCCCCAGAATAAGATTACAG-3′ (SEQ ID NO: 5313)5′-AGACCCCCCAGAAUAAGAUUACAgt-3′ (SEQ ID NO: 1286)3′-UGUCUGGGGGGUCUUAUUCUAAUGUCA-5′ (SEQ ID NO: 3300) LDHA-346 Target:5′-ACAGACCCCCCAGAATAAGATTACAGT-3′ (SEQ ID NO: 5314)5′-GACCCCCCAGAAUAAGAUUACAGtt-3′ (SEQ ID NO: 1287)3′-GUCUGGGGGGUCUUAUUCUAAUGUCAA-5′ (SEQ ID NO: 3301) LDHA-347 Target:5′-CAGACCCCCCAGAATAAGATTACAGTT-3′ (SEQ ID NO: 5315)5′-ACCCCCCAGAAUAAGAUUACAGUtg-3′ (SEQ ID NO: 1288)3′-UCUGGGGGGUCUUAUUCUAAUGUCAAC-5′ (SEQ ID NO: 3302) LDHA-348 Target:5′-AGACCCCCCAGAATAAGATTACAGTTG-3′ (SEQ ID NO: 5316)5′-CCCCCCAGAAUAAGAUUACAGUUgt-3′ (SEQ ID NO: 1289)3′-CUGGGGGGUCUUAUUCUAAUGUCAACA-5′ (SEQ ID NO: 3303) LDHA-349 Target:5′-GACCCCCCAGAATAAGATTACAGTTGT-3′ (SEQ ID NO: 5317)5′-CCCCCAGAAUAAGAUUACAGUUGtt-3′ (SEQ ID NO: 1290)3′-UGGGGGGUCUUAUUCUAAUGUCAACAA-5′ (SEQ ID NO: 3304) LDHA-350 Target:5′-ACCCCCCAGAATAAGATTACAGTTGTT-3′ (SEQ ID NO: 5318)5′-CCCCAGAAUAAGAUUACAGUUGUtg-3′ (SEQ ID NO: 1291)3′-GGGGGGUCUUAUUCUAAUGUCAACAAC-5′ (SEQ ID NO: 3305) LDHA-351 Target:5′-CCCCCCAGAATAAGATTACAGTTGTTG-3′ (SEQ ID NO: 5319)5′-CCCAGAAUAAGAUUACAGUUGUUgg-3′ (SEQ ID NO: 1292)3′-GGGGGUCUUAUUCUAAUGUCAACAACC-5′ (SEQ ID NO: 3306) LDHA-352 Target:5′-CCCCCAGAATAAGATTACAGTTGTTGG-3′ (SEQ ID NO: 5320)5′-CCAGAAUAAGAUUACAGUUGUUGgg-3′ (SEQ ID NO: 1293)3′-GGGGUCUUAUUCUAAUGUCAACAACCC-5′ (SEQ ID NO: 3307) LDHA-353 Target:5′-CCCCAGAATAAGATTACAGTTGTTGGG-3′ (SEQ ID NO: 5321)5′-CAGAAUAAGAUUACAGUUGUUGGgg-3′ (SEQ ID NO: 1294)3′-GGGUCUUAUUCUAAUGUCAACAACCCC-5′ (SEQ ID NO: 3308) LDHA-354 Target:5′-CCCAGAATAAGATTACAGTTGTTGGGG-3′ (SEQ ID NO: 5322)5′-AAUAAGAUUACAGUUGUUGGGGUtg-3′ (SEQ ID NO: 1295)3′-UCUUAUUCUAAUGUCAACAACCCCAAC-5′ (SEQ ID NO: 3309) LDHA-357 Target:5′-AGAATAAGATTACAGTTGTTGGGGTTG-3′ (SEQ ID NO: 5323)5′-AUAAGAUUACAGUUGUUGGGGUUgg-3′ (SEQ ID NO: 1296)3′-CUUAUUCUAAUGUCAACAACCCCAACC-5′ (SEQ ID NO: 3310) LDHA-358 Target:5′-GAATAAGATTACAGTTGTTGGGGTTGG-3′ (SEQ ID NO: 5324)5′-UAAGAUUACAGUUGUUGGGGUUGgt-3′ (SEQ ID NO: 1297)3′-UUAUUCUAAUGUCAACAACCCCAACCA-5′ (SEQ ID NO: 3311) LDHA-359 Target:5′-AATAAGATTACAGTTGTTGGGGTTGGT-3′ (SEQ ID NO: 5325)5′-AGUUGUUGGGGUUGGUGCUGUUGgc-3′ (SEQ ID NO: 1298)3′-UGUCAACAACCCCAACCACGACAACCG-5′ (SEQ ID NO: 3312) LDHA-368 Target:5′-ACAGTTGTTGGGGTTGGTGCTGTTGGC-3′ (SEQ ID NO: 5326)5′-UGUUGGGGUUGGUGCUGUUGGCAtg-3′ (SEQ ID NO: 1299)3′-CAACAACCCCAACCACGACAACCGUAC-5′ (SEQ ID NO: 3313) LDHA-371 Target:5′-GTTGTTGGGGTTGGTGCTGTTGGCATG-3′ (SEQ ID NO: 5327)5′-GUUGGGGUUGGUGCUGUUGGCAUgg-3′ (SEQ ID NO: 1300)3′-AACAACCCCAACCACGACAACCGUACC-5′ (SEQ ID NO: 3314) LDHA-372 Target:5′-TTGTTGGGGTTGGTGCTGTTGGCATGG-3′ (SEQ ID NO: 5328)5′-UUGGGGUUGGUGCUGUUGGCAUGgc-3′ (SEQ ID NO: 1301)3′-ACAACCCCAACCACGACAACCGUACCG-5′ (SEQ ID NO: 3315) LDHA-373 Target:5′-TGTTGGGGTTGGTGCTGTTGGCATGGC-3′ (SEQ ID NO: 5329)5′-UGGGGUUGGUGCUGUUGGCAUGGcc-3′ (SEQ ID NO: 1302)3′-CAACCCCAACCACGACAACCGUACCGG-5′ (SEQ ID NO: 3316) LDHA-374 Target:5′-GTTGGGGTTGGTGCTGTTGGCATGGCC-3′ (SEQ ID NO: 5330)5′-GGGGUUGGUGCUGUUGGCAUGGCct-3′ (SEQ ID NO: 1303)3′-AACCCCAACCACGACAACCGUACCGGA-5′ (SEQ ID NO: 3317) LDHA-375 Target:5′-TTGGGGTTGGTGCTGTTGGCATGGCCT-3′ (SEQ ID NO: 5331)5′-GGGUUGGUGCUGUUGGCAUGGCCtg-3′ (SEQ ID NO: 1304)3′-ACCCCAACCACGACAACCGUACCGGAC-5′ (SEQ ID NO: 3318) LDHA-376 Target:5′-TGGGGTTGGTGCTGTTGGCATGGCCTG-3′ (SEQ ID NO: 5332)5′-GGUUGGUGCUGUUGGCAUGGCCUgt-3′ (SEQ ID NO: 1305)3′-CCCCAACCACGACAACCGUACCGGACA-5′ (SEQ ID NO: 3319) LDHA-377 Target:5′-GGGGTTGGTGCTGTTGGCATGGCCTGT-3′ (SEQ ID NO: 5333)5′-GUUGGUGCUGUUGGCAUGGCCUGtg-3′ (SEQ ID NO: 1306)3′-CCCAACCACGACAACCGUACCGGACAC-5′ (SEQ ID NO: 3320) LDHA-378 Target:5′-GGGTTGGTGCTGTTGGCATGGCCTGTG-3′ (SEQ ID NO: 5334)5′-UUGGUGCUGUUGGCAUGGCCUGUgc-3′ (SEQ ID NO: 1307)3′-CCAACCACGACAACCGUACCGGACACG-5′ (SEQ ID NO: 3321) LDHA-379 Target:5′-GGTTGGTGCTGTTGGCATGGCCTGTGC-3′ (SEQ ID NO: 5335)5′-UGGUGCUGUUGGCAUGGCCUGUGcc-3′ (SEQ ID NO: 1308)3′-CAACCACGACAACCGUACCGGACACGG-5′ (SEQ ID NO: 3322) LDHA-380 Target:5′-GTTGGTGCTGTTGGCATGGCCTGTGCC-3′ (SEQ ID NO: 5336)5′-GGUGCUGUUGGCAUGGCCUGUGCca-3′ (SEQ ID NO: 1309)3′-AACCACGACAACCGUACCGGACACGGU-5′ (SEQ ID NO: 3323) LDHA-381 Target:5′-TTGGTGCTGTTGGCATGGCCTGTGCCA-3′ (SEQ ID NO: 5337)5′-GUGCUGUUGGCAUGGCCUGUGCCat-3′ (SEQ ID NO: 1310)3′-ACCACGACAACCGUACCGGACACGGUA-5′ (SEQ ID NO: 3324) LDHA-382 Target:5′-TGGTGCTGTTGGCATGGCCTGTGCCAT-3′ (SEQ ID NO: 5338)5′-UGCUGUUGGCAUGGCCUGUGCCAtc-3′ (SEQ ID NO: 1311)3′-CCACGACAACCGUACCGGACACGGUAG-5′ (SEQ ID NO: 3325) LDHA-383 Target:5′-GGTGCTGTTGGCATGGCCTGTGCCATC-3′ (SEQ ID NO: 5339)5′-GCUGUUGGCAUGGCCUGUGCCAUca-3′ (SEQ ID NO: 1312)3′-CACGACAACCGUACCGGACACGGUAGU-5′ (SEQ ID NO: 3326) LDHA-384 Target:5′-GTGCTGTTGGCATGGCCTGTGCCATCA-3′ (SEQ ID NO: 5340)5′-CUGUUGGCAUGGCCUGUGCCAUCag-3′ (SEQ ID NO: 1313)3′-ACGACAACCGUACCGGACACGGUAGUC-5′ (SEQ ID NO: 3327) LDHA-385 Target:5′-TGCTGTTGGCATGGCCTGTGCCATCAG-3′ (SEQ ID NO: 5341)5′-UGUUGGCAUGGCCUGUGCCAUCAgt-3′ (SEQ ID NO: 1314)3′-CGACAACCGUACCGGACACGGUAGUCA-5′ (SEQ ID NO: 3328) LDHA-386 Target:5′-GCTGTTGGCATGGCCTGTGCCATCAGT-3′ (SEQ ID NO: 5342)5′-GUUGGCAUGGCCUGUGCCAUCAGta-3′ (SEQ ID NO: 1315)3′-GACAACCGUACCGGACACGGUAGUCAU-5′ (SEQ ID NO: 3329) LDHA-387 Target:5′-CTGTTGGCATGGCCTGTGCCATCAGTA-3′ (SEQ ID NO: 5343)5′-UUGGCAUGGCCUGUGCCAUCAGUat-3′ (SEQ ID NO: 1316)3′-ACAACCGUACCGGACACGGUAGUCAUA-5′ (SEQ ID NO: 3330) LDHA-388 Target:5′-TGTTGGCATGGCCTGTGCCATCAGTAT-3′ (SEQ ID NO: 5344)5′-UGGCAUGGCCUGUGCCAUCAGUAtc-3′ (SEQ ID NO: 1317)3′-CAACCGUACCGGACACGGUAGUCAUAG-5′ (SEQ ID NO: 3331) LDHA-389 Target:5′-GTTGGCATGGCCTGTGCCATCAGTATC-3′ (SEQ ID NO: 5345)5′-GGCAUGGCCUGUGCCAUCAGUAUct-3′ (SEQ ID NO: 1318)3′-AACCGUACCGGACACGGUAGUCAUAGA-5′ (SEQ ID NO: 3332) LDHA-390 Target:5′-TTGGCATGGCCTGTGCCATCAGTATCT-3′ (SEQ ID NO: 5346)5′-GCAUGGCCUGUGCCAUCAGUAUCtt-3′ (SEQ ID NO: 1319)3′-ACCGUACCGGACACGGUAGUCAUAGAA-5′ (SEQ ID NO: 3333) LDHA-391 Target:5′-TGGCATGGCCTGTGCCATCAGTATCTT-3′ (SEQ ID NO: 5347)5′-CAUGGCCUGUGCCAUCAGUAUCUta-3′ (SEQ ID NO: 1320)3′-CCGUACCGGACACGGUAGUCAUAGAAU-5′ (SEQ ID NO: 3334) LDHA-392 Target:5′-GGCATGGCCTGTGCCATCAGTATCTTA-3′ (SEQ ID NO: 5348)5′-AUGGCCUGUGCCAUCAGUAUCUUaa-3′ (SEQ ID NO: 1321)3′-CGUACCGGACACGGUAGUCAUAGAAUU-5′ (SEQ ID NO: 3335) LDHA-393 Target:5′-GCATGGCCTGTGCCATCAGTATCTTAA-3′ (SEQ ID NO: 5349)5′-UGGCCUGUGCCAUCAGUAUCUUAat-3′ (SEQ ID NO: 1322)3′-GUACCGGACACGGUAGUCAUAGAAUUA-5′ (SEQ ID NO: 3336) LDHA-394 Target:5′-CATGGCCTGTGCCATCAGTATCTTAAT-3′ (SEQ ID NO: 5350)5′-GGCCUGUGCCAUCAGUAUCUUAAtg-3′ (SEQ ID NO: 1323)3′-UACCGGACACGGUAGUCAUAGAAUUAC-5′ (SEQ ID NO: 3337) LDHA-395 Target:5′-ATGGCCTGTGCCATCAGTATCTTAATG-3′ (SEQ ID NO: 5351)5′-GCCUGUGCCAUCAGUAUCUUAAUga-3′ (SEQ ID NO: 1324)3′-ACCGGACACGGUAGUCAUAGAAUUACU-5′ (SEQ ID NO: 3338) LDHA-396 Target:5′-TGGCCTGTGCCATCAGTATCTTAATGA-3′ (SEQ ID NO: 5352)5′-AUCAGUAUCUUAAUGAAGGACUUgg-3′ (SEQ ID NO: 1325)3′-GGUAGUCAUAGAAUUACUUCCUGAACC-5′ (SEQ ID NO: 3339) LDHA-405 Target:5′-CCATCAGTATCTTAATGAAGGACTTGG-3′ (SEQ ID NO: 5353)5′-UCAGUAUCUUAAUGAAGGACUUGgc-3′ (SEQ ID NO: 1326)3′-GUAGUCAUAGAAUUACUUCCUGAACCG-5′ (SEQ ID NO: 3340) LDHA-406 Target:5′-CATCAGTATCTTAATGAAGGACTTGGC-3′ (SEQ ID NO: 5354)5′-CAGUAUCUUAAUGAAGGACUUGGca-3′ (SEQ ID NO: 1327)3′-UAGUCAUAGAAUUACUUCCUGAACCGU-5′ (SEQ ID NO: 3341) LDHA-407 Target:5′-ATCAGTATCTTAATGAAGGACTTGGCA-3′ (SEQ ID NO: 5355)5′-AGUAUCUUAAUGAAGGACUUGGCag-3′ (SEQ ID NO: 1328)3′-AGUCAUAGAAUUACUUCCUGAACCGUC-5′ (SEQ ID NO: 3342) LDHA-408 Target:5′-TCAGTATCTTAATGAAGGACTTGGCAG-3′ (SEQ ID NO: 5356)5′-GUAUCUUAAUGAAGGACUUGGCAga-3′ (SEQ ID NO: 1329)3′-GUCAUAGAAUUACUUCCUGAACCGUCU-5′ (SEQ ID NO: 3343) LDHA-409 Target:5′-CAGTATCTTAATGAAGGACTTGGCAGA-3′ (SEQ ID NO: 5357)5′-UAUCUUAAUGAAGGACUUGGCAGat-3′ (SEQ ID NO: 1330)3′-UCAUAGAAUUACUUCCUGAACCGUCUA-5′ (SEQ ID NO: 3344) LDHA-410 Target:5′-AGTATCTTAATGAAGGACTTGGCAGAT-3′ (SEQ ID NO: 5358)5′-AUCUUAAUGAAGGACUUGGCAGAtg-3′ (SEQ ID NO: 1331)3′-CAUAGAAUUACUUCCUGAACCGUCUAC-5′ (SEQ ID NO: 3345) LDHA-411 Target:5′-GTATCTTAATGAAGGACTTGGCAGATG-3′ (SEQ ID NO: 5359)5′-UCUUAAUGAAGGACUUGGCAGAUga-3′ (SEQ ID NO: 1332)3′-AUAGAAUUACUUCCUGAACCGUCUACU-5′ (SEQ ID NO: 3346) LDHA-412 Target:5′-TATCTTAATGAAGGACTTGGCAGATGA-3′ (SEQ ID NO: 5360)5′-CUUAAUGAAGGACUUGGCAGAUGaa-3′ (SEQ ID NO: 1333)3′-UAGAAUUACUUCCUGAACCGUCUACUU-5′ (SEQ ID NO: 3347) LDHA-413 Target:5′-ATCTTAATGAAGGACTTGGCAGATGAA-3′ (SEQ ID NO: 5361)5′-UUAAUGAAGGACUUGGCAGAUGAac-3′ (SEQ ID NO: 1334)3′-AGAAUUACUUCCUGAACCGUCUACUUG-5′ (SEQ ID NO: 3348) LDHA-414 Target:5′-TCTTAATGAAGGACTTGGCAGATGAAC-3′ (SEQ ID NO: 5362)5′-UAAUGAAGGACUUGGCAGAUGAAct-3′ (SEQ ID NO: 1335)3′-GAAUUACUUCCUGAACCGUCUACUUGA-5′ (SEQ ID NO: 3349) LDHA-415 Target:5′-CTTAATGAAGGACTTGGCAGATGAACT-3′ (SEQ ID NO: 5363)5′-AAUGAAGGACUUGGCAGAUGAACtt-3′ (SEQ ID NO: 1336)3′-AAUUACUUCCUGAACCGUCUACUUGAA-5′ (SEQ ID NO: 3350) LDHA-416 Target:5′-TTAATGAAGGACTTGGCAGATGAACTT-3′ (SEQ ID NO: 5364)5′-AUGAAGGACUUGGCAGAUGAACUtg-3′ (SEQ ID NO: 1337)3′-AUUACUUCCUGAACCGUCUACUUGAAC-5′ (SEQ ID NO: 3351) LDHA-417 Target:5′-TAATGAAGGACTTGGCAGATGAACTTG-3′ (SEQ ID NO: 5365)5′-UGAAGGACUUGGCAGAUGAACUUgc-3′ (SEQ ID NO: 1338)3′-UUACUUCCUGAACCGUCUACUUGAACG-5′ (SEQ ID NO: 3352) LDHA-418 Target:5′-AATGAAGGACTTGGCAGATGAACTTGC-3′ (SEQ ID NO: 5366)5′-GAAGGACUUGGCAGAUGAACUUGct-3′ (SEQ ID NO: 1339)3′-UACUUCCUGAACCGUCUACUUGAACGA-5′ (SEQ ID NO: 3353) LDHA-419 Target:5′-ATGAAGGACTTGGCAGATGAACTTGCT-3′ (SEQ ID NO: 5367)5′-AAGGACUUGGCAGAUGAACUUGCtc-3′ (SEQ ID NO: 1340)3′-ACUUCCUGAACCGUCUACUUGAACGAG-5′ (SEQ ID NO: 3354) LDHA-420 Target:5′-TGAAGGACTTGGCAGATGAACTTGCTC-3′ (SEQ ID NO: 5368)5′-AGGACUUGGCAGAUGAACUUGCUct-3′ (SEQ ID NO: 1341)3′-CUUCCUGAACCGUCUACUUGAACGAGA-5′ (SEQ ID NO: 3355) LDHA-421 Target:5′-GAAGGACTTGGCAGATGAACTTGCTCT-3′ (SEQ ID NO: 5369)5′-GGACUUGGCAGAUGAACUUGCUCtt-3′ (SEQ ID NO: 1342)3′-UUCCUGAACCGUCUACUUGAACGAGAA-5′ (SEQ ID NO: 3356) LDHA-422 Target:5′-AAGGACTTGGCAGATGAACTTGCTCTT-3′ (SEQ ID NO: 5370)5′-GACUUGGCAGAUGAACUUGCUCUtg-3′ (SEQ ID NO: 1343)3′-UCCUGAACCGUCUACUUGAACGAGAAC-5′ (SEQ ID NO: 3357) LDHA-423 Target:5′-AGGACTTGGCAGATGAACTTGCTCTTG-3′ (SEQ ID NO: 5371)5′-ACUUGGCAGAUGAACUUGCUCUUgt-3′ (SEQ ID NO: 1344)3′-CCUGAACCGUCUACUUGAACGAGAACA-5′ (SEQ ID NO: 3358) LDHA-424 Target:5′-GGACTTGGCAGATGAACTTGCTCTTGT-3′ (SEQ ID NO: 5372)5′-CUUGGCAGAUGAACUUGCUCUUGtt-3′ (SEQ ID NO: 1345)3′-CUGAACCGUCUACUUGAACGAGAACAA-5′ (SEQ ID NO: 3359) LDHA-425 Target:5′-GACTTGGCAGATGAACTTGCTCTTGTT-3′ (SEQ ID NO: 5373)5′-UUGGCAGAUGAACUUGCUCUUGUtg-3′ (SEQ ID NO: 1346)3′-UGAACCGUCUACUUGAACGAGAACAAC-5′ (SEQ ID NO: 3360) LDHA-426 Target:5′-ACTTGGCAGATGAACTTGCTCTTGTTG-3′ (SEQ ID NO: 5374)5′-UGGCAGAUGAACUUGCUCUUGUUga-3′ (SEQ ID NO: 1347)3′-GAACCGUCUACUUGAACGAGAACAACU-5′ (SEQ ID NO: 3361) LDHA-427 Target:5′-CTTGGCAGATGAACTTGCTCTTGTTGA-3′ (SEQ ID NO: 5375)5′-GGCAGAUGAACUUGCUCUUGUUGat-3′ (SEQ ID NO: 1348)3′-AACCGUCUACUUGAACGAGAACAACUA-5′ (SEQ ID NO: 3362) LDHA-428 Target:5′-TTGGCAGATGAACTTGCTCTTGTTGAT-3′ (SEQ ID NO: 5376)5′-GCAGAUGAACUUGCUCUUGUUGAtg-3′ (SEQ ID NO: 1349)3′-ACCGUCUACUUGAACGAGAACAACUAC-5′ (SEQ ID NO: 3363) LDHA-429 Target:5′-TGGCAGATGAACTTGCTCTTGTTGATG-3′ (SEQ ID NO: 5377)5′-CAGAUGAACUUGCUCUUGUUGAUgt-3′ (SEQ ID NO: 1350)3′-CCGUCUACUUGAACGAGAACAACUACA-5′ (SEQ ID NO: 3364) LDHA-430 Target:5′-GGCAGATGAACTTGCTCTTGTTGATGT-3′ (SEQ ID NO: 5378)5′-AGAUGAACUUGCUCUUGUUGAUGtc-3′ (SEQ ID NO: 1351)3′-CGUCUACUUGAACGAGAACAACUACAG-5′ (SEQ ID NO: 3365) LDHA-431 Target:5′-GCAGATGAACTTGCTCTTGTTGATGTC-3′ (SEQ ID NO: 5379)5′-GAUGAACUUGCUCUUGUUGAUGUca-3′ (SEQ ID NO: 1352)3′-GUCUACUUGAACGAGAACAACUACAGU-5′ (SEQ ID NO: 3366) LDHA-432 Target:5′-CAGATGAACTTGCTCTTGTTGATGTCA-3′ (SEQ ID NO: 5380)5′-AUGAACUUGCUCUUGUUGAUGUCat-3′ (SEQ ID NO: 1353)3′-UCUACUUGAACGAGAACAACUACAGUA-5′ (SEQ ID NO: 3367) LDHA-433 Target:5′-AGATGAACTTGCTCTTGTTGATGTCAT-3′ (SEQ ID NO: 5381)5′-UGAACUUGCUCUUGUUGAUGUCAtc-3′ (SEQ ID NO: 1354)3′-CUACUUGAACGAGAACAACUACAGUAG-5′ (SEQ ID NO: 3368) LDHA-434 Target:5′-GATGAACTTGCTCTTGTTGATGTCATC-3′ (SEQ ID NO: 5382)5′-GAACUUGCUCUUGUUGAUGUCAUcg-3′ (SEQ ID NO: 1355)3′-UACUUGAACGAGAACAACUACAGUAGC-5′ (SEQ ID NO: 3369) LDHA-435 Target:5′-ATGAACTTGCTCTTGTTGATGTCATCG-3′ (SEQ ID NO: 5383)5′-AACUUGCUCUUGUUGAUGUCAUCga-3′ (SEQ ID NO: 1356)3′-ACUUGAACGAGAACAACUACAGUAGCU-5′ (SEQ ID NO: 3370) LDHA-436 Target:5′-TGAACTTGCTCTTGTTGATGTCATCGA-3′ (SEQ ID NO: 5384)5′-ACUUGCUCUUGUUGAUGUCAUCGaa-3′ (SEQ ID NO: 1357)3′-CUUGAACGAGAACAACUACAGUAGCUU-5′ (SEQ ID NO: 3371) LDHA-437 Target:5′-GAACTTGCTCTTGTTGATGTCATCGAA-3′ (SEQ ID NO: 5385)5′-CUUGCUCUUGUUGAUGUCAUCGAag-3′ (SEQ ID NO: 1358)3′-UUGAACGAGAACAACUACAGUAGCUUC-5′ (SEQ ID NO: 3372) LDHA-438 Target:5′-AACTTGCTCTTGTTGATGTCATCGAAG-3′ (SEQ ID NO: 5386)5′-UUGCUCUUGUUGAUGUCAUCGAAga-3′ (SEQ ID NO: 1359)3′-UGAACGAGAACAACUACAGUAGCUUCU-5′ (SEQ ID NO: 3373) LDHA-439 Target:5′-ACTTGCTCTTGTTGATGTCATCGAAGA-3′ (SEQ ID NO: 5387)5′-UGCUCUUGUUGAUGUCAUCGAAGac-3′ (SEQ ID NO: 1360)3′-GAACGAGAACAACUACAGUAGCUUCUG-5′ (SEQ ID NO: 3374) LDHA-440 Target:5′-CTTGCTCTTGTTGATGTCATCGAAGAC-3′ (SEQ ID NO: 5388)5′-GCUCUUGUUGAUGUCAUCGAAGAca-3′ (SEQ ID NO: 1361)3′-AACGAGAACAACUACAGUAGCUUCUGU-5′ (SEQ ID NO: 3375) LDHA-441 Target:5′-TTGCTCTTGTTGATGTCATCGAAGACA-3′ (SEQ ID NO: 5389)5′-CUCUUGUUGAUGUCAUCGAAGACaa-3′ (SEQ ID NO: 1362)3′-ACGAGAACAACUACAGUAGCUUCUGUU-5′ (SEQ ID NO: 3376) LDHA-442 Target:5′-TGCTCTTGTTGATGTCATCGAAGACAA-3′ (SEQ ID NO: 5390)5′-UCUUGUUGAUGUCAUCGAAGACAaa-3′ (SEQ ID NO: 1363)3′-CGAGAACAACUACAGUAGCUUCUGUUU-5′ (SEQ ID NO: 3377) LDHA-443 Target:5′-GCTCTTGTTGATGTCATCGAAGACAAA-3′ (SEQ ID NO: 5391)5′-CUUGUUGAUGUCAUCGAAGACAAat-3′ (SEQ ID NO: 1364)3′-GAGAACAACUACAGUAGCUUCUGUUUA-5′ (SEQ ID NO: 3378) LDHA-444 Target:5′-CTCTTGTTGATGTCATCGAAGACAAAT-3′ (SEQ ID NO: 5392)5′-UUGUUGAUGUCAUCGAAGACAAAtt-3′ (SEQ ID NO: 1365)3′-AGAACAACUACAGUAGCUUCUGUUUAA-5′ (SEQ ID NO: 3379) LDHA-445 Target:5′-TCTTGTTGATGTCATCGAAGACAAATT-3′ (SEQ ID NO: 5393)5′-UGUUGAUGUCAUCGAAGACAAAUtg-3′ (SEQ ID NO: 1366)3′-GAACAACUACAGUAGCUUCUGUUUAAC-5′ (SEQ ID NO: 3380) LDHA-446 Target:5′-CTTGTTGATGTCATCGAAGACAAATTG-3′ (SEQ ID NO: 5394)5′-GUUGAUGUCAUCGAAGACAAAUUga-3′ (SEQ ID NO: 1367)3′-AACAACUACAGUAGCUUCUGUUUAACU-5′ (SEQ ID NO: 3381) LDHA-447 Target:5′-TTGTTGATGTCATCGAAGACAAATTGA-3′ (SEQ ID NO: 5395)5′-UUGAUGUCAUCGAAGACAAAUUGaa-3′ (SEQ ID NO: 1368)3′-ACAACUACAGUAGCUUCUGUUUAACUU-5′ (SEQ ID NO: 3382) LDHA-448 Target:5′-TGTTGATGTCATCGAAGACAAATTGAA-3′ (SEQ ID NO: 5396)5′-UGAUGUCAUCGAAGACAAAUUGAag-3′ (SEQ ID NO: 1369)3′-CAACUACAGUAGCUUCUGUUUAACUUC-5′ (SEQ ID NO: 3383) LDHA-449 Target:5′-GTTGATGTCATCGAAGACAAATTGAAG-3′ (SEQ ID NO: 5397)5′-GAUGUCAUCGAAGACAAAUUGAAgg-3′ (SEQ ID NO: 1370)3′-AACUACAGUAGCUUCUGUUUAACUUCC-5′ (SEQ ID NO: 3384) LDHA-450 Target:5′-TTGATGTCATCGAAGACAAATTGAAGG-3′ (SEQ ID NO: 5398)5′-AUGUCAUCGAAGACAAAUUGAAGgg-3′ (SEQ ID NO: 1371)3′-ACUACAGUAGCUUCUGUUUAACUUCCC-5′ (SEQ ID NO: 3385) LDHA-451 Target:5′-TGATGTCATCGAAGACAAATTGAAGGG-3′ (SEQ ID NO: 5399)5′-UGUCAUCGAAGACAAAUUGAAGGga-3′ (SEQ ID NO: 1372)3′-CUACAGUAGCUUCUGUUUAACUUCCCU-5′ (SEQ ID NO: 3386) LDHA-452 Target:5′-GATGTCATCGAAGACAAATTGAAGGGA-3′ (SEQ ID NO: 5400)5′-GUCAUCGAAGACAAAUUGAAGGGag-3′ (SEQ ID NO: 1373)3′-UACAGUAGCUUCUGUUUAACUUCCCUC-5′ (SEQ ID NO: 3387) LDHA-453 Target:5′-ATGTCATCGAAGACAAATTGAAGGGAG-3′ (SEQ ID NO: 5401)5′-UCAUCGAAGACAAAUUGAAGGGAga-3′ (SEQ ID NO: 1374)3′-ACAGUAGCUUCUGUUUAACUUCCCUCU-5′ (SEQ ID NO: 3388) LDHA-454 Target:5′-TGTCATCGAAGACAAATTGAAGGGAGA-3′ (SEQ ID NO: 5402)5′-CAUCGAAGACAAAUUGAAGGGAGag-3′ (SEQ ID NO: 1375)3′-CAGUAGCUUCUGUUUAACUUCCCUCUC-5′ (SEQ ID NO: 3389) LDHA-455 Target:5′-GTCATCGAAGACAAATTGAAGGGAGAG-3′ (SEQ ID NO: 5403)5′-AUCGAAGACAAAUUGAAGGGAGAga-3′ (SEQ ID NO: 1376)3′-AGUAGCUUCUGUUUAACUUCCCUCUCU-5′ (SEQ ID NO: 3390) LDHA-456 Target:5′-TCATCGAAGACAAATTGAAGGGAGAGA-3′ (SEQ ID NO: 5404)5′-UCGAAGACAAAUUGAAGGGAGAGat-3′ (SEQ ID NO: 1377)3′-GUAGCUUCUGUUUAACUUCCCUCUCUA-5′ (SEQ ID NO: 3391) LDHA-457 Target:5′-CATCGAAGACAAATTGAAGGGAGAGAT-3′ (SEQ ID NO: 5405)5′-CGAAGACAAAUUGAAGGGAGAGAtg-3′ (SEQ ID NO: 1378)3′-UAGCUUCUGUUUAACUUCCCUCUCUAC-5′ (SEQ ID NO: 3392) LDHA-458 Target:5′-ATCGAAGACAAATTGAAGGGAGAGATG-3′ (SEQ ID NO: 5406)5′-GAAGACAAAUUGAAGGGAGAGAUga-3′ (SEQ ID NO: 1379)3′-AGCUUCUGUUUAACUUCCCUCUCUACU-5′ (SEQ ID NO: 3393) LDHA-459 Target:5′-TCGAAGACAAATTGAAGGGAGAGATGA-3′ (SEQ ID NO: 5407)5′-AAGACAAAUUGAAGGGAGAGAUGat-3′ (SEQ ID NO: 1380)3′-GCUUCUGUUUAACUUCCCUCUCUACUA-5′ (SEQ ID NO: 3394) LDHA-460 Target:5′-CGAAGACAAATTGAAGGGAGAGATGAT-3′ (SEQ ID NO: 5408)5′-AGACAAAUUGAAGGGAGAGAUGAtg-3′ (SEQ ID NO: 1381)3′-CUUCUGUUUAACUUCCCUCUCUACUAC-5′ (SEQ ID NO: 3395) LDHA-461 Target:5′-GAAGACAAATTGAAGGGAGAGATGATG-3′ (SEQ ID NO: 5409)5′-GACAAAUUGAAGGGAGAGAUGAUgg-3′ (SEQ ID NO: 1382)3′-UUCUGUUUAACUUCCCUCUCUACUACC-5′ (SEQ ID NO: 3396) LDHA-462 Target:5′-AAGACAAATTGAAGGGAGAGATGATGG-3′ (SEQ ID NO: 5410)5′-ACAAAUUGAAGGGAGAGAUGAUGga-3′ (SEQ ID NO: 1383)3′-UCUGUUUAACUUCCCUCUCUACUACCU-5′ (SEQ ID NO: 3397) LDHA-463 Target:5′-AGACAAATTGAAGGGAGAGATGATGGA-3′ (SEQ ID NO: 5411)5′-CAAAUUGAAGGGAGAGAUGAUGGat-3′ (SEQ ID NO: 1384)3′-CUGUUUAACUUCCCUCUCUACUACCUA-5′ (SEQ ID NO: 3398) LDHA-464 Target:5′-GACAAATTGAAGGGAGAGATGATGGAT-3′ (SEQ ID NO: 5412)5′-AAAUUGAAGGGAGAGAUGAUGGAtc-3′ (SEQ ID NO: 1385)3′-UGUUUAACUUCCCUCUCUACUACCUAG-5′ (SEQ ID NO: 3399) LDHA-465 Target:5′-ACAAATTGAAGGGAGAGATGATGGATC-3′ (SEQ ID NO: 5413)5′-AAUUGAAGGGAGAGAUGAUGGAUct-3′ (SEQ ID NO: 1386)3′-GUUUAACUUCCCUCUCUACUACCUAGA-5′ (SEQ ID NO: 3400) LDHA-466 Target:5′-CAAATTGAAGGGAGAGATGATGGATCT-3′ (SEQ ID NO: 5414)5′-AUUGAAGGGAGAGAUGAUGGAUCtc-3′ (SEQ ID NO: 1387)3′-UUUAACUUCCCUCUCUACUACCUAGAG-5′ (SEQ ID NO: 3401) LDHA-467 Target:5′-AAATTGAAGGGAGAGATGATGGATCTC-3′ (SEQ ID NO: 5415)5′-UUGAAGGGAGAGAUGAUGGAUCUcc-3′ (SEQ ID NO: 1388)3′-UUAACUUCCCUCUCUACUACCUAGAGG-5′ (SEQ ID NO: 3402) LDHA-468 Target:5′-AATTGAAGGGAGAGATGATGGATCTCC-3′ (SEQ ID NO: 5416)5′-UGAAGGGAGAGAUGAUGGAUCUCca-3′ (SEQ ID NO: 1389)3′-UAACUUCCCUCUCUACUACCUAGAGGU-5′ (SEQ ID NO: 3403) LDHA-469 Target:5′-ATTGAAGGGAGAGATGATGGATCTCCA-3′ (SEQ ID NO: 5417)5′-GAAGGGAGAGAUGAUGGAUCUCCaa-3′ (SEQ ID NO: 1390)3′-AACUUCCCUCUCUACUACCUAGAGGUU-5′ (SEQ ID NO: 3404) LDHA-470 Target:5′-TTGAAGGGAGAGATGATGGATCTCCAA-3′ (SEQ ID NO: 5418)5′-AAGGGAGAGAUGAUGGAUCUCCAac-3′ (SEQ ID NO: 1391)3′-ACUUCCCUCUCUACUACCUAGAGGUUG-5′ (SEQ ID NO: 3405) LDHA-471 Target:5′-TGAAGGGAGAGATGATGGATCTCCAAC-3′ (SEQ ID NO: 5419)5′-AGGGAGAGAUGAUGGAUCUCCAAca-3′ (SEQ ID NO: 1392)3′-CUUCCCUCUCUACUACCUAGAGGUUGU-5′ (SEQ ID NO: 3406) LDHA-472 Target:5′-GAAGGGAGAGATGATGGATCTCCAACA-3′ (SEQ ID NO: 5420)5′-GGGAGAGAUGAUGGAUCUCCAACat-3′ (SEQ ID NO: 1393)3′-UUCCCUCUCUACUACCUAGAGGUUGUA-5′ (SEQ ID NO: 3407) LDHA-473 Target:5′-AAGGGAGAGATGATGGATCTCCAACAT-3′ (SEQ ID NO: 5421)5′-GGAGAGAUGAUGGAUCUCCAACAtg-3′ (SEQ ID NO: 1394)3′-UCCCUCUCUACUACCUAGAGGUUGUAC-5′ (SEQ ID NO: 3408) LDHA-474 Target:5′-AGGGAGAGATGATGGATCTCCAACATG-3′ (SEQ ID NO: 5422)5′-GAGAGAUGAUGGAUCUCCAACAUgg-3′ (SEQ ID NO: 1395)3′-CCCUCUCUACUACCUAGAGGUUGUACC-5′ (SEQ ID NO: 3409) LDHA-475 Target:5′-GGGAGAGATGATGGATCTCCAACATGG-3′ (SEQ ID NO: 5423)5′-AGAGAUGAUGGAUCUCCAACAUGgc-3′ (SEQ ID NO: 1396)3′-CCUCUCUACUACCUAGAGGUUGUACCG-5′ (SEQ ID NO: 3410) LDHA-476 Target:5′-GGAGAGATGATGGATCTCCAACATGGC-3′ (SEQ ID NO: 5424)5′-GAGAUGAUGGAUCUCCAACAUGGca-3′ (SEQ ID NO: 1397)3′-CUCUCUACUACCUAGAGGUUGUACCGU-5′ (SEQ ID NO: 3411) LDHA-477 Target:5′-GAGAGATGATGGATCTCCAACATGGCA-3′ (SEQ ID NO: 5425)5′-AGAUGAUGGAUCUCCAACAUGGCag-3′ (SEQ ID NO: 1398)3′-UCUCUACUACCUAGAGGUUGUACCGUC-5′ (SEQ ID NO: 3412) LDHA-478 Target:5′-AGAGATGATGGATCTCCAACATGGCAG-3′ (SEQ ID NO: 5426)5′-GAUGAUGGAUCUCCAACAUGGCAgc-3′ (SEQ ID NO: 1399)3′-CUCUACUACCUAGAGGUUGUACCGUCG-5′ (SEQ ID NO: 3413) LDHA-479 Target:5′-GAGATGATGGATCTCCAACATGGCAGC-3′ (SEQ ID NO: 5427)5′-AUGAUGGAUCUCCAACAUGGCAGcc-3′ (SEQ ID NO: 1400)3′-UCUACUACCUAGAGGUUGUACCGUCGG-5′ (SEQ ID NO: 3414) LDHA-480 Target:5′-AGATGATGGATCTCCAACATGGCAGCC-3′ (SEQ ID NO: 5428)5′-UGAUGGAUCUCCAACAUGGCAGCct-3′ (SEQ ID NO: 1401)3′-CUACUACCUAGAGGUUGUACCGUCGGA-5′ (SEQ ID NO: 3415) LDHA-481 Target:5′-GATGATGGATCTCCAACATGGCAGCCT-3′ (SEQ ID NO: 5429)5′-GAUGGAUCUCCAACAUGGCAGCCtt-3′ (SEQ ID NO: 1402)3′-UACUACCUAGAGGUUGUACCGUCGGAA-5′ (SEQ ID NO: 3416) LDHA-482 Target:5′-ATGATGGATCTCCAACATGGCAGCCTT-3′ (SEQ ID NO: 5430)5′-AUGGAUCUCCAACAUGGCAGCCUtt-3′ (SEQ ID NO: 1403)3′-ACUACCUAGAGGUUGUACCGUCGGAAA-5′ (SEQ ID NO: 3417) LDHA-483 Target:5′-TGATGGATCTCCAACATGGCAGCCTTT-3′ (SEQ ID NO: 5431)5′-UGGAUCUCCAACAUGGCAGCCUUtt-3′ (SEQ ID NO: 1404)3′-CUACCUAGAGGUUGUACCGUCGGAAAA-5′ (SEQ ID NO: 3418) LDHA-484 Target:5′-GATGGATCTCCAACATGGCAGCCTTTT-3′ (SEQ ID NO: 5432)5′-GGAUCUCCAACAUGGCAGCCUUUtc-3′ (SEQ ID NO: 1405)3′-UACCUAGAGGUUGUACCGUCGGAAAAG-5′ (SEQ ID NO: 3419) LDHA-485 Target:5′-ATGGATCTCCAACATGGCAGCCTTTTC-3′ (SEQ ID NO: 5433)5′-GAUCUCCAACAUGGCAGCCUUUUcc-3′ (SEQ ID NO: 1406)3′-ACCUAGAGGUUGUACCGUCGGAAAAGG-5′ (SEQ ID NO: 3420) LDHA-486 Target:5′-TGGATCTCCAACATGGCAGCCTTTTCC-3′ (SEQ ID NO: 5434)5′-AUCUCCAACAUGGCAGCCUUUUCct-3′ (SEQ ID NO: 1407)3′-CCUAGAGGUUGUACCGUCGGAAAAGGA-5′ (SEQ ID NO: 3421) LDHA-487 Target:5′-GGATCTCCAACATGGCAGCCTTTTCCT-3′ (SEQ ID NO: 5435)5′-UCUCCAACAUGGCAGCCUUUUCCtt-3′ (SEQ ID NO: 1408)3′-CUAGAGGUUGUACCGUCGGAAAAGGAA-5′ (SEQ ID NO: 3422) LDHA-488 Target:5′-GATCTCCAACATGGCAGCCTTTTCCTT-3′ (SEQ ID NO: 5436)5′-CUCCAACAUGGCAGCCUUUUCCUta-3′ (SEQ ID NO: 1409)3′-UAGAGGUUGUACCGUCGGAAAAGGAAU-5′ (SEQ ID NO: 3423) LDHA-489 Target:5′-ATCTCCAACATGGCAGCCTTTTCCTTA-3′ (SEQ ID NO: 5437)5′-UCCAACAUGGCAGCCUUUUCCUUag-3′ (SEQ ID NO: 1410)3′-AGAGGUUGUACCGUCGGAAAAGGAAUC-5′ (SEQ ID NO: 3424) LDHA-490 Target:5′-TCTCCAACATGGCAGCCTTTTCCTTAG-3′ (SEQ ID NO: 5438)5′-CCAACAUGGCAGCCUUUUCCUUAga-3′ (SEQ ID NO: 1411)3′-GAGGUUGUACCGUCGGAAAAGGAAUCU-5′ (SEQ ID NO: 3425) LDHA-491 Target:5′-CTCCAACATGGCAGCCTTTTCCTTAGA-3′ (SEQ ID NO: 5439)5′-CAACAUGGCAGCCUUUUCCUUAGaa-3′ (SEQ ID NO: 1412)3′-AGGUUGUACCGUCGGAAAAGGAAUCUU-5′ (SEQ ID NO: 3426) LDHA-492 Target:5′-TCCAACATGGCAGCCTTTTCCTTAGAA-3′ (SEQ ID NO: 5440)5′-AACAUGGCAGCCUUUUCCUUAGAac-3′ (SEQ ID NO: 1413)3′-GGUUGUACCGUCGGAAAAGGAAUCUUG-5′ (SEQ ID NO: 3427) LDHA-493 Target:5′-CCAACATGGCAGCCTTTTCCTTAGAAC-3′ (SEQ ID NO: 5441)5′-ACAUGGCAGCCUUUUCCUUAGAAca-3′ (SEQ ID NO: 1414)3′-GUUGUACCGUCGGAAAAGGAAUCUUGU-5′ (SEQ ID NO: 3428) LDHA-494 Target:5′-CAACATGGCAGCCTTTTCCTTAGAACA-3′ (SEQ ID NO: 5442)5′-CAUGGCAGCCUUUUCCUUAGAACac-3′ (SEQ ID NO: 1415)3′-UUGUACCGUCGGAAAAGGAAUCUUGUG-5′ (SEQ ID NO: 3429) LDHA-495 Target:5′-AACATGGCAGCCTTTTCCTTAGAACAC-3′ (SEQ ID NO: 5443)5′-AUGGCAGCCUUUUCCUUAGAACAcc-3′ (SEQ ID NO: 1416)3′-UGUACCGUCGGAAAAGGAAUCUUGUGG-5′ (SEQ ID NO: 3430) LDHA-496 Target:5′-ACATGGCAGCCTTTTCCTTAGAACACC-3′ (SEQ ID NO: 5444)5′-UGGCAGCCUUUUCCUUAGAACACca-3′ (SEQ ID NO: 1417)3′-GUACCGUCGGAAAAGGAAUCUUGUGGU-5′ (SEQ ID NO: 3431) LDHA-497 Target:5′-CATGGCAGCCTTTTCCTTAGAACACCA-3′ (SEQ ID NO: 5445)5′-GGCAGCCUUUUCCUUAGAACACCaa-3′ (SEQ ID NO: 1418)3′-UACCGUCGGAAAAGGAAUCUUGUGGUU-5′ (SEQ ID NO: 3432) LDHA-498 Target:5′-ATGGCAGCCTTTTCCTTAGAACACCAA-3′ (SEQ ID NO: 5446)5′-GCAGCCUUUUCCUUAGAACACCAaa-3′ (SEQ ID NO: 1419)3′-ACCGUCGGAAAAGGAAUCUUGUGGUUU-5′ (SEQ ID NO: 3433) LDHA-499 Target:5′-TGGCAGCCTTTTCCTTAGAACACCAAA-3′ (SEQ ID NO: 5447)5′-CAGCCUUUUCCUUAGAACACCAAag-3′ (SEQ ID NO: 1420)3′-CCGUCGGAAAAGGAAUCUUGUGGUUUC-5′ (SEQ ID NO: 3434) LDHA-500 Target:5′-GGCAGCCTTTTCCTTAGAACACCAAAG-3′ (SEQ ID NO: 5448)5′-AGCCUUUUCCUUAGAACACCAAAga-3′ (SEQ ID NO: 1421)3′-CGUCGGAAAAGGAAUCUUGUGGUUUCU-5′ (SEQ ID NO: 3435) LDHA-501 Target:5′-GCAGCCTTTTCCTTAGAACACCAAAGA-3′ (SEQ ID NO: 5449)5′-GCCUUUUCCUUAGAACACCAAAGat-3′ (SEQ ID NO: 1422)3′-GUCGGAAAAGGAAUCUUGUGGUUUCUA-5′ (SEQ ID NO: 3436) LDHA-502 Target:5′-CAGCCTTTTCCTTAGAACACCAAAGAT-3′ (SEQ ID NO: 5450)5′-CCUUUUCCUUAGAACACCAAAGAtt-3′ (SEQ ID NO: 1423)3′-UCGGAAAAGGAAUCUUGUGGUUUCUAA-5′ (SEQ ID NO: 3437) LDHA-503 Target:5′-AGCCTTTTCCTTAGAACACCAAAGATT-3′ (SEQ ID NO: 5451)5′-CUUUUCCUUAGAACACCAAAGAUtg-3′ (SEQ ID NO: 1424)3′-CGGAAAAGGAAUCUUGUGGUUUCUAAC-5′ (SEQ ID NO: 3438) LDHA-504 Target:5′-GCCTTTTCCTTAGAACACCAAAGATTG-3′ (SEQ ID NO: 5452)5′-UUUUCCUUAGAACACCAAAGAUUgt-3′ (SEQ ID NO: 1425)3′-GGAAAAGGAAUCUUGUGGUUUCUAACA-5′ (SEQ ID NO: 3439) LDHA-505 Target:5′-CCTTTTCCTTAGAACACCAAAGATTGT-3′ (SEQ ID NO: 5453)5′-UUUCCUUAGAACACCAAAGAUUGtc-3′ (SEQ ID NO: 1426)3′-GAAAAGGAAUCUUGUGGUUUCUAACAG-5′ (SEQ ID NO: 3440) LDHA-506 Target:5′-CTTTTCCTTAGAACACCAAAGATTGTC-3′ (SEQ ID NO: 5454)5′-UUCCUUAGAACACCAAAGAUUGUct-3′ (SEQ ID NO: 1427)3′-AAAAGGAAUCUUGUGGUUUCUAACAGA-5′ (SEQ ID NO: 3441) LDHA-507 Target:5′-TTTTCCTTAGAACACCAAAGATTGTCT-3′ (SEQ ID NO: 5455)5′-UCCUUAGAACACCAAAGAUUGUCtc-3′ (SEQ ID NO: 1428)3′-AAAGGAAUCUUGUGGUUUCUAACAGAG-5′ (SEQ ID NO: 3442) LDHA-508 Target:5′-TTTCCTTAGAACACCAAAGATTGTCTC-3′ (SEQ ID NO: 5456)5′-CCUUAGAACACCAAAGAUUGUCUct-3′ (SEQ ID NO: 1429)3′-AAGGAAUCUUGUGGUUUCUAACAGAGA-5′ (SEQ ID NO: 3443) LDHA-509 Target:5′-TTCCTTAGAACACCAAAGATTGTCTCT-3′ (SEQ ID NO: 5457)5′-CUUAGAACACCAAAGAUUGUCUCtg-3′ (SEQ ID NO: 1430)3′-AGGAAUCUUGUGGUUUCUAACAGAGAC-5′ (SEQ ID NO: 3444) LDHA-510 Target:5′-TCCTTAGAACACCAAAGATTGTCTCTG-3′ (SEQ ID NO: 5458)5′-UUAGAACACCAAAGAUUGUCUCUgg-3′ (SEQ ID NO: 1431)3′-GGAAUCUUGUGGUUUCUAACAGAGACC-5′ (SEQ ID NO: 3445) LDHA-511 Target:5′-CCTTAGAACACCAAAGATTGTCTCTGG-3′ (SEQ ID NO: 5459)5′-UAGAACACCAAAGAUUGUCUCUGgc-3′ (SEQ ID NO: 1432)3′-GAAUCUUGUGGUUUCUAACAGAGACCG-5′ (SEQ ID NO: 3446) LDHA-512 Target:5′-CTTAGAACACCAAAGATTGTCTCTGGC-3′ (SEQ ID NO: 5460)5′-AGAACACCAAAGAUUGUCUCUGGca-3′ (SEQ ID NO: 1433)3′-AAUCUUGUGGUUUCUAACAGAGACCGU-5′ (SEQ ID NO: 3447) LDHA-513 Target:5′-TTAGAACACCAAAGATTGTCTCTGGCA-3′ (SEQ ID NO: 5461)5′-GAACACCAAAGAUUGUCUCUGGCaa-3′ (SEQ ID NO: 1434)3′-AUCUUGUGGUUUCUAACAGAGACCGUU-5′ (SEQ ID NO: 3448) LDHA-514 Target:5′-TAGAACACCAAAGATTGTCTCTGGCAA-3′ (SEQ ID NO: 5462)5′-AACACCAAAGAUUGUCUCUGGCAaa-3′ (SEQ ID NO: 1435)3′-UCUUGUGGUUUCUAACAGAGACCGUUU-5′ (SEQ ID NO: 3449) LDHA-515 Target:5′-AGAACACCAAAGATTGTCTCTGGCAAA-3′ (SEQ ID NO: 5463)5′-ACACCAAAGAUUGUCUCUGGCAAag-3′ (SEQ ID NO: 1436)3′-CUUGUGGUUUCUAACAGAGACCGUUUC-5′ (SEQ ID NO: 3450) LDHA-516 Target:5′-GAACACCAAAGATTGTCTCTGGCAAAG-3′ (SEQ ID NO: 5464)5′-CACCAAAGAUUGUCUCUGGCAAAga-3′ (SEQ ID NO: 1437)3′-UUGUGGUUUCUAACAGAGACCGUUUCU-5′ (SEQ ID NO: 3451) LDHA-517 Target:5′-AACACCAAAGATTGTCTCTGGCAAAGA-3′ (SEQ ID NO: 5465)5′-ACCAAAGAUUGUCUCUGGCAAAGac-3′ (SEQ ID NO: 1438)3′-UGUGGUUUCUAACAGAGACCGUUUCUG-5′ (SEQ ID NO: 3452) LDHA-518 Target:5′-ACACCAAAGATTGTCTCTGGCAAAGAC-3′ (SEQ ID NO: 5466)5′-CCAAAGAUUGUCUCUGGCAAAGAct-3′ (SEQ ID NO: 1439)3′-GUGGUUUCUAACAGAGACCGUUUCUGA-5′ (SEQ ID NO: 3453) LDHA-519 Target:5′-CACCAAAGATTGTCTCTGGCAAAGACT-3′ (SEQ ID NO: 5467)5′-CAAAGAUUGUCUCUGGCAAAGACta-3′ (SEQ ID NO: 1440)3′-UGGUUUCUAACAGAGACCGUUUCUGAU-5′ (SEQ ID NO: 3454) LDHA-520 Target:5′-ACCAAAGATTGTCTCTGGCAAAGACTA-3′ (SEQ ID NO: 5468)5′-AAAGAUUGUCUCUGGCAAAGACUat-3′ (SEQ ID NO: 1441)3′-GGUUUCUAACAGAGACCGUUUCUGAUA-5′ (SEQ ID NO: 3455) LDHA-521 Target:5′-CCAAAGATTGTCTCTGGCAAAGACTAT-3′ (SEQ ID NO: 5469)5′-AAGAUUGUCUCUGGCAAAGACUAta-3′ (SEQ ID NO: 1442)3′-GUUUCUAACAGAGACCGUUUCUGAUAU-5′ (SEQ ID NO: 3456) LDHA-522 Target:5′-CAAAGATTGTCTCTGGCAAAGACTATA-3′ (SEQ ID NO: 5470)5′-AGAUUGUCUCUGGCAAAGACUAUaa-3′ (SEQ ID NO: 1443)3′-UUUCUAACAGAGACCGUUUCUGAUAUU-5′ (SEQ ID NO: 3457) LDHA-523 Target:5′-AAAGATTGTCTCTGGCAAAGACTATAA-3′ (SEQ ID NO: 5471)5′-GAUUGUCUCUGGCAAAGACUAUAat-3′ (SEQ ID NO: 1444)3′-UUCUAACAGAGACCGUUUCUGAUAUUA-5′ (SEQ ID NO: 3458) LDHA-524 Target:5′-AAGATTGTCTCTGGCAAAGACTATAAT-3′ (SEQ ID NO: 5472)5′-AUUGUCUCUGGCAAAGACUAUAAtg-3′ (SEQ ID NO: 1445)3′-UCUAACAGAGACCGUUUCUGAUAUUAC-5′ (SEQ ID NO: 3459) LDHA-525 Target:5′-AGATTGTCTCTGGCAAAGACTATAATG-3′ (SEQ ID NO: 5473)5′-UUGUCUCUGGCAAAGACUAUAAUgt-3′ (SEQ ID NO: 1446)3′-CUAACAGAGACCGUUUCUGAUAUUACA-5′ (SEQ ID NO: 3460) LDHA-526 Target:5′-GATTGTCTCTGGCAAAGACTATAATGT-3′ (SEQ ID NO: 5474)5′-UGUCUCUGGCAAAGACUAUAAUGta-3′ (SEQ ID NO: 1447)3′-UAACAGAGACCGUUUCUGAUAUUACAU-5′ (SEQ ID NO: 3461) LDHA-527 Target:5′-ATTGTCTCTGGCAAAGACTATAATGTA-3′ (SEQ ID NO: 5475)5′-GUCUCUGGCAAAGACUAUAAUGUaa-3′ (SEQ ID NO: 1448)3′-AACAGAGACCGUUUCUGAUAUUACAUU-5′ (SEQ ID NO: 3462) LDHA-528 Target:5′-TTGTCTCTGGCAAAGACTATAATGTAA-3′ (SEQ ID NO: 5476)5′-UCUCUGGCAAAGACUAUAAUGUAac-3′ (SEQ ID NO: 1449)3′-ACAGAGACCGUUUCUGAUAUUACAUUG-5′ (SEQ ID NO: 3463) LDHA-529 Target:5′-TGTCTCTGGCAAAGACTATAATGTAAC-3′ (SEQ ID NO: 5477)5′-CUCUGGCAAAGACUAUAAUGUAAct-3′ (SEQ ID NO: 1450)3′-CAGAGACCGUUUCUGAUAUUACAUUGA-5′ (SEQ ID NO: 3464) LDHA-530 Target:5′-GTCTCTGGCAAAGACTATAATGTAACT-3′ (SEQ ID NO: 5478)5′-UCUGGCAAAGACUAUAAUGUAACtg-3′ (SEQ ID NO: 1451)3′-AGAGACCGUUUCUGAUAUUACAUUGAC-5′ (SEQ ID NO: 3465) LDHA-531 Target:5′-TCTCTGGCAAAGACTATAATGTAACTG-3′ (SEQ ID NO: 5479)5′-CUGGCAAAGACUAUAAUGUAACUgc-3′ (SEQ ID NO: 1452)3′-GAGACCGUUUCUGAUAUUACAUUGACG-5′ (SEQ ID NO: 3466) LDHA-532 Target:5′-CTCTGGCAAAGACTATAATGTAACTGC-3′ (SEQ ID NO: 5480)5′-UGGCAAAGACUAUAAUGUAACUGca-3′ (SEQ ID NO: 1453)3′-AGACCGUUUCUGAUAUUACAUUGACGU-5′ (SEQ ID NO: 3467) LDHA-533 Target:5′-TCTGGCAAAGACTATAATGTAACTGCA-3′ (SEQ ID NO: 5481)5′-GGCAAAGACUAUAAUGUAACUGCaa-3′ (SEQ ID NO: 1454)3′-GACCGUUUCUGAUAUUACAUUGACGUU-5′ (SEQ ID NO: 3468) LDHA-534 Target:5′-CTGGCAAAGACTATAATGTAACTGCAA-3′ (SEQ ID NO: 5482)5′-GCAAAGACUAUAAUGUAACUGCAaa-3′ (SEQ ID NO: 1455)3′-ACCGUUUCUGAUAUUACAUUGACGUUU-5′ (SEQ ID NO: 3469) LDHA-535 Target:5′-TGGCAAAGACTATAATGTAACTGCAAA-3′ (SEQ ID NO: 5483)5′-CAAAGACUAUAAUGUAACUGCAAac-3′ (SEQ ID NO: 1456)3′-CCGUUUCUGAUAUUACAUUGACGUUUG-5′ (SEQ ID NO: 3470) LDHA-536 Target:5′-GGCAAAGACTATAATGTAACTGCAAAC-3′ (SEQ ID NO: 5484)5′-AAAGACUAUAAUGUAACUGCAAAct-3′ (SEQ ID NO: 1457)3′-CGUUUCUGAUAUUACAUUGACGUUUGA-5′ (SEQ ID NO: 3471) LDHA-537 Target:5′-GCAAAGACTATAATGTAACTGCAAACT-3′ (SEQ ID NO: 5485)5′-AAGACUAUAAUGUAACUGCAAACtc-3′ (SEQ ID NO: 1458)3′-GUUUCUGAUAUUACAUUGACGUUUGAG-5′ (SEQ ID NO: 3472) LDHA-538 Target:5′-CAAAGACTATAATGTAACTGCAAACTC-3′ (SEQ ID NO: 5486)5′-AGACUAUAAUGUAACUGCAAACUcc-3′ (SEQ ID NO: 1459)3′-UUUCUGAUAUUACAUUGACGUUUGAGG-5′ (SEQ ID NO: 3473) LDHA-539 Target:5′-AAAGACTATAATGTAACTGCAAACTCC-3′ (SEQ ID NO: 5487)5′-GACUAUAAUGUAACUGCAAACUCca-3′ (SEQ ID NO: 1460)3′-UUCUGAUAUUACAUUGACGUUUGAGGU-5′ (SEQ ID NO: 3474) LDHA-540 Target:5′-AAGACTATAATGTAACTGCAAACTCCA-3′ (SEQ ID NO: 5488)5′-ACUAUAAUGUAACUGCAAACUCCaa-3′ (SEQ ID NO: 1461)3′-UCUGAUAUUACAUUGACGUUUGAGGUU-5′ (SEQ ID NO: 3475) LDHA-541 Target:5′-AGACTATAATGTAACTGCAAACTCCAA-3′ (SEQ ID NO: 5489)5′-CUAUAAUGUAACUGCAAACUCCAag-3′ (SEQ ID NO: 1462)3′-CUGAUAUUACAUUGACGUUUGAGGUUC-5′ (SEQ ID NO: 3476) LDHA-542 Target:5′-GACTATAATGTAACTGCAAACTCCAAG-3′ (SEQ ID NO: 5490)5′-UAUAAUGUAACUGCAAACUCCAAgc-3′ (SEQ ID NO: 1463)3′-UGAUAUUACAUUGACGUUUGAGGUUCG-5′ (SEQ ID NO: 3477) LDHA-543 Target:5′-ACTATAATGTAACTGCAAACTCCAAGC-3′ (SEQ ID NO: 5491)5′-AUAAUGUAACUGCAAACUCCAAGct-3′ (SEQ ID NO: 1464)3′-GAUAUUACAUUGACGUUUGAGGUUCGA-5′ (SEQ ID NO: 3478) LDHA-544 Target:5′-CTATAATGTAACTGCAAACTCCAAGCT-3′ (SEQ ID NO: 5492)5′-UAAUGUAACUGCAAACUCCAAGCtg-3′ (SEQ ID NO: 1465)3′-AUAUUACAUUGACGUUUGAGGUUCGAC-5′ (SEQ ID NO: 3479) LDHA-545 Target:5′-TATAATGTAACTGCAAACTCCAAGCTG-3′ (SEQ ID NO: 5493)5′-AAUGUAACUGCAAACUCCAAGCUgg-3′ (SEQ ID NO: 1466)3′-UAUUACAUUGACGUUUGAGGUUCGACC-5′ (SEQ ID NO: 3480) LDHA-546 Target:5′-ATAATGTAACTGCAAACTCCAAGCTGG-3′ (SEQ ID NO: 5494)5′-AUGUAACUGCAAACUCCAAGCUGgt-3′ (SEQ ID NO: 1467)3′-AUUACAUUGACGUUUGAGGUUCGACCA-5′ (SEQ ID NO: 3481) LDHA-547 Target:5′-TAATGTAACTGCAAACTCCAAGCTGGT-3′ (SEQ ID NO: 5495)5′-UGUAACUGCAAACUCCAAGCUGGtc-3′ (SEQ ID NO: 1468)3′-UUACAUUGACGUUUGAGGUUCGACCAG-5′ (SEQ ID NO: 3482) LDHA-548 Target:5′-AATGTAACTGCAAACTCCAAGCTGGTC-3′ (SEQ ID NO: 5496)5′-GUAACUGCAAACUCCAAGCUGGUca-3′ (SEQ ID NO: 1469)3′-UACAUUGACGUUUGAGGUUCGACCAGU-5′ (SEQ ID NO: 3483) LDHA-549 Target:5′-ATGTAACTGCAAACTCCAAGCTGGTCA-3′ (SEQ ID NO: 5497)5′-UAACUGCAAACUCCAAGCUGGUCat-3′ (SEQ ID NO: 1470)3′-ACAUUGACGUUUGAGGUUCGACCAGUA-5′ (SEQ ID NO: 3484) LDHA-550 Target:5′-TGTAACTGCAAACTCCAAGCTGGTCAT-3′ (SEQ ID NO: 5498)5′-AACUGCAAACUCCAAGCUGGUCAtt-3′ (SEQ ID NO: 1471)3′-CAUUGACGUUUGAGGUUCGACCAGUAA-5′ (SEQ ID NO: 3485) LDHA-551 Target:5′-GTAACTGCAAACTCCAAGCTGGTCATT-3′ (SEQ ID NO: 5499)5′-ACUGCAAACUCCAAGCUGGUCAUta-3′ (SEQ ID NO: 1472)3′-AUUGACGUUUGAGGUUCGACCAGUAAU-5′ (SEQ ID NO: 3486) LDHA-552 Target:5′-TAACTGCAAACTCCAAGCTGGTCATTA-3′ (SEQ ID NO: 5500)5′-CUGCAAACUCCAAGCUGGUCAUUat-3′ (SEQ ID NO: 1473)3′-UUGACGUUUGAGGUUCGACCAGUAAUA-5′ (SEQ ID NO: 3487) LDHA-553 Target:5′-AACTGCAAACTCCAAGCTGGTCATTAT-3′ (SEQ ID NO: 5501)5′-UGCAAACUCCAAGCUGGUCAUUAtc-3′ (SEQ ID NO: 1474)3′-UGACGUUUGAGGUUCGACCAGUAAUAG-5′ (SEQ ID NO: 3488) LDHA-554 Target:5′-ACTGCAAACTCCAAGCTGGTCATTATC-3′ (SEQ ID NO: 5502)5′-GCAAACUCCAAGCUGGUCAUUAUca-3′ (SEQ ID NO: 1475)3′-GACGUUUGAGGUUCGACCAGUAAUAGU-5′ (SEQ ID NO: 3489) LDHA-555 Target:5′-CTGCAAACTCCAAGCTGGTCATTATCA-3′ (SEQ ID NO: 5503)5′-CAAACUCCAAGCUGGUCAUUAUCac-3′ (SEQ ID NO: 1476)3′-ACGUUUGAGGUUCGACCAGUAAUAGUG-5′ (SEQ ID NO: 3490) LDHA-556 Target:5′-TGCAAACTCCAAGCTGGTCATTATCAC-3′ (SEQ ID NO: 5504)5′-AAACUCCAAGCUGGUCAUUAUCAcg-3′ (SEQ ID NO: 1477)3′-CGUUUGAGGUUCGACCAGUAAUAGUGC-5′ (SEQ ID NO: 3491) LDHA-557 Target:5′-GCAAACTCCAAGCTGGTCATTATCACG-3′ (SEQ ID NO: 5505)5′-AACUCCAAGCUGGUCAUUAUCACgg-3′ (SEQ ID NO: 1478)3′-GUUUGAGGUUCGACCAGUAAUAGUGCC-5′ (SEQ ID NO: 3492) LDHA-558 Target:5′-CAAACTCCAAGCTGGTCATTATCACGG-3′ (SEQ ID NO: 5506)5′-ACUCCAAGCUGGUCAUUAUCACGgc-3′ (SEQ ID NO: 1479)3′-UUUGAGGUUCGACCAGUAAUAGUGCCG-5′ (SEQ ID NO: 3493) LDHA-559 Target:5′-AAACTCCAAGCTGGTCATTATCACGGC-3′ (SEQ ID NO: 5507)5′-CUCCAAGCUGGUCAUUAUCACGGct-3′ (SEQ ID NO: 1480)3′-UUGAGGUUCGACCAGUAAUAGUGCCGA-5′ (SEQ ID NO: 3494) LDHA-560 Target:5′-AACTCCAAGCTGGTCATTATCACGGCT-3′ (SEQ ID NO: 5508)5′-UCCAAGCUGGUCAUUAUCACGGCtg-3′ (SEQ ID NO: 1481)3′-UGAGGUUCGACCAGUAAUAGUGCCGAC-5′ (SEQ ID NO: 3495) LDHA-561 Target:5′-ACTCCAAGCTGGTCATTATCACGGCTG-3′ (SEQ ID NO: 5509)5′-CCAAGCUGGUCAUUAUCACGGCUgg-3′ (SEQ ID NO: 1482)3′-GAGGUUCGACCAGUAAUAGUGCCGACC-5′ (SEQ ID NO: 3496) LDHA-562 Target:5′-CTCCAAGCTGGTCATTATCACGGCTGG-3′ (SEQ ID NO: 5510)5′-CAAGCUGGUCAUUAUCACGGCUGgg-3′ (SEQ ID NO: 1483)3′-AGGUUCGACCAGUAAUAGUGCCGACCC-5′ (SEQ ID NO: 3497) LDHA-563 Target:5′-TCCAAGCTGGTCATTATCACGGCTGGG-3′ (SEQ ID NO: 5511)5′-AAGCUGGUCAUUAUCACGGCUGGgg-3′ (SEQ ID NO: 1484)3′-GGUUCGACCAGUAAUAGUGCCGACCCC-5′ (SEQ ID NO: 3498) LDHA-564 Target:5′-CCAAGCTGGTCATTATCACGGCTGGGG-3′ (SEQ ID NO: 5512)5′-AGCUGGUCAUUAUCACGGCUGGGgc-3′ (SEQ ID NO: 1485)3′-GUUCGACCAGUAAUAGUGCCGACCCCG-5′ (SEQ ID NO: 3499) LDHA-565 Target:5′-CAAGCTGGTCATTATCACGGCTGGGGC-3′ (SEQ ID NO: 5513)5′-GCUGGUCAUUAUCACGGCUGGGGca-3′ (SEQ ID NO: 1486)3′-UUCGACCAGUAAUAGUGCCGACCCCGU-5′ (SEQ ID NO: 3500) LDHA-566 Target:5′-AAGCTGGTCATTATCACGGCTGGGGCA-3′ (SEQ ID NO: 5514)5′-CUGGUCAUUAUCACGGCUGGGGCac-3′ (SEQ ID NO: 1487)3′-UCGACCAGUAAUAGUGCCGACCCCGUG-5′ (SEQ ID NO: 3501) LDHA-567 Target:5′-AGCTGGTCATTATCACGGCTGGGGCAC-3′ (SEQ ID NO: 5515)5′-UGGUCAUUAUCACGGCUGGGGCAcg-3′ (SEQ ID NO: 1488)3′-CGACCAGUAAUAGUGCCGACCCCGUGC-5′ (SEQ ID NO: 3502) LDHA-568 Target:5′-GCTGGTCATTATCACGGCTGGGGCACG-3′ (SEQ ID NO: 5516)5′-GGUCAUUAUCACGGCUGGGGCACgt-3′ (SEQ ID NO: 1489)3′-GACCAGUAAUAGUGCCGACCCCGUGCA-5′ (SEQ ID NO: 3503) LDHA-569 Target:5′-CTGGTCATTATCACGGCTGGGGCACGT-3′ (SEQ ID NO: 5517)5′-GUCAUUAUCACGGCUGGGGCACGtc-3′ (SEQ ID NO: 1490)3′-ACCAGUAAUAGUGCCGACCCCGUGCAG-5′ (SEQ ID NO: 3504) LDHA-570 Target:5′-TGGTCATTATCACGGCTGGGGCACGTC-3′ (SEQ ID NO: 5518)5′-UCAUUAUCACGGCUGGGGCACGUca-3′ (SEQ ID NO: 1491)3′-CCAGUAAUAGUGCCGACCCCGUGCAGU-5′ (SEQ ID NO: 3505) LDHA-571 Target:5′-GGTCATTATCACGGCTGGGGCACGTCA-3′ (SEQ ID NO: 5519)5′-CAUUAUCACGGCUGGGGCACGUCag-3′ (SEQ ID NO: 1492)3′-CAGUAAUAGUGCCGACCCCGUGCAGUC-5′ (SEQ ID NO: 3506) LDHA-572 Target:5′-GTCATTATCACGGCTGGGGCACGTCAG-3′ (SEQ ID NO: 5520)5′-AUUAUCACGGCUGGGGCACGUCAgc-3′ (SEQ ID NO: 1493)3′-AGUAAUAGUGCCGACCCCGUGCAGUCG-5′ (SEQ ID NO: 3507) LDHA-573 Target:5′-TCATTATCACGGCTGGGGCACGTCAGC-3′ (SEQ ID NO: 5521)5′-UUAUCACGGCUGGGGCACGUCAGca-3′ (SEQ ID NO: 1494)3′-GUAAUAGUGCCGACCCCGUGCAGUCGU-5′ (SEQ ID NO: 3508) LDHA-574 Target:5′-CATTATCACGGCTGGGGCACGTCAGCA-3′ (SEQ ID NO: 5522)5′-UAUCACGGCUGGGGCACGUCAGCaa-3′ (SEQ ID NO: 1495)3′-UAAUAGUGCCGACCCCGUGCAGUCGUU-5′ (SEQ ID NO: 3509) LDHA-575 Target:5′-ATTATCACGGCTGGGGCACGTCAGCAA-3′ (SEQ ID NO: 5523)5′-AUCACGGCUGGGGCACGUCAGCAag-3′ (SEQ ID NO: 1496)3′-AAUAGUGCCGACCCCGUGCAGUCGUUC-5′ (SEQ ID NO: 3510) LDHA-576 Target:5′-TTATCACGGCTGGGGCACGTCAGCAAG-3′ (SEQ ID NO: 5524)5′-UCACGGCUGGGGCACGUCAGCAAga-3′ (SEQ ID NO: 1497)3′-AUAGUGCCGACCCCGUGCAGUCGUUCU-5′ (SEQ ID NO: 3511) LDHA-577 Target:5′-TATCACGGCTGGGGCACGTCAGCAAGA-3′ (SEQ ID NO: 5525)5′-CACGGCUGGGGCACGUCAGCAAGag-3′ (SEQ ID NO: 1498)3′-UAGUGCCGACCCCGUGCAGUCGUUCUC-5′ (SEQ ID NO: 3512) LDHA-578 Target:5′-ATCACGGCTGGGGCACGTCAGCAAGAG-3′ (SEQ ID NO: 5526)5′-ACGGCUGGGGCACGUCAGCAAGAgg-3′ (SEQ ID NO: 1499)3′-AGUGCCGACCCCGUGCAGUCGUUCUCC-5′ (SEQ ID NO: 3513) LDHA-579 Target:5′-TCACGGCTGGGGCACGTCAGCAAGAGG-3′ (SEQ ID NO: 5527)5′-CGGCUGGGGCACGUCAGCAAGAGgg-3′ (SEQ ID NO: 1500)3′-GUGCCGACCCCGUGCAGUCGUUCUCCC-5′ (SEQ ID NO: 3514) LDHA-580 Target:5′-CACGGCTGGGGCACGTCAGCAAGAGGG-3′ (SEQ ID NO: 5528)5′-GGCUGGGGCACGUCAGCAAGAGGga-3′ (SEQ ID NO: 1501)3′-UGCCGACCCCGUGCAGUCGUUCUCCCU-5′ (SEQ ID NO: 3515) LDHA-581 Target:5′-ACGGCTGGGGCACGTCAGCAAGAGGGA-3′ (SEQ ID NO: 5529)5′-GCUGGGGCACGUCAGCAAGAGGGag-3′ (SEQ ID NO: 1502)3′-GCCGACCCCGUGCAGUCGUUCUCCCUC-5′ (SEQ ID NO: 3516) LDHA-582 Target:5′-CGGCTGGGGCACGTCAGCAAGAGGGAG-3′ (SEQ ID NO: 5530)5′-CUGGGGCACGUCAGCAAGAGGGAga-3′ (SEQ ID NO: 1503)3′-CCGACCCCGUGCAGUCGUUCUCCCUCU-5′ (SEQ ID NO: 3517) LDHA-583 Target:5′-GGCTGGGGCACGTCAGCAAGAGGGAGA-3′ (SEQ ID NO: 5531)5′-UGGGGCACGUCAGCAAGAGGGAGaa-3′ (SEQ ID NO: 1504)3′-CGACCCCGUGCAGUCGUUCUCCCUCUU-5′ (SEQ ID NO: 3518) LDHA-584 Target:5′-GCTGGGGCACGTCAGCAAGAGGGAGAA-3′ (SEQ ID NO: 5532)5′-GGGGCACGUCAGCAAGAGGGAGAaa-3′ (SEQ ID NO: 1505)3′-GACCCCGUGCAGUCGUUCUCCCUCUUU-5′ (SEQ ID NO: 3519) LDHA-585 Target:5′-CTGGGGCACGTCAGCAAGAGGGAGAAA-3′ (SEQ ID NO: 5533)5′-GGGCACGUCAGCAAGAGGGAGAAag-3′ (SEQ ID NO: 1506)3′-ACCCCGUGCAGUCGUUCUCCCUCUUUC-5′ (SEQ ID NO: 3520) LDHA-586 Target:5′-TGGGGCACGTCAGCAAGAGGGAGAAAG-3′ (SEQ ID NO: 5534)5′-GGCACGUCAGCAAGAGGGAGAAAgc-3′ (SEQ ID NO: 1507)3′-CCCCGUGCAGUCGUUCUCCCUCUUUCG-5′ (SEQ ID NO: 3521) LDHA-587 Target:5′-GGGGCACGTCAGCAAGAGGGAGAAAGC-3′ (SEQ ID NO: 5535)5′-GCACGUCAGCAAGAGGGAGAAAGcc-3′ (SEQ ID NO: 1508)3′-CCCGUGCAGUCGUUCUCCCUCUUUCGG-5′ (SEQ ID NO: 3522) LDHA-588 Target:5′-GGGCACGTCAGCAAGAGGGAGAAAGCC-3′ (SEQ ID NO: 5536)5′-CACGUCAGCAAGAGGGAGAAAGCcg-3′ (SEQ ID NO: 1509)3′-CCGUGCAGUCGUUCUCCCUCUUUCGGC-5′ (SEQ ID NO: 3523) LDHA-589 Target:5′-GGCACGTCAGCAAGAGGGAGAAAGCCG-3′ (SEQ ID NO: 5537)5′-ACGUCAGCAAGAGGGAGAAAGCCgt-3′ (SEQ ID NO: 1510)3′-CGUGCAGUCGUUCUCCCUCUUUCGGCA-5′ (SEQ ID NO: 3524) LDHA-590 Target:5′-GCACGTCAGCAAGAGGGAGAAAGCCGT-3′ (SEQ ID NO: 5538)5′-CGUCAGCAAGAGGGAGAAAGCCGtc-3′ (SEQ ID NO: 1511)3′-GUGCAGUCGUUCUCCCUCUUUCGGCAG-5′ (SEQ ID NO: 3525) LDHA-591 Target:5′-CACGTCAGCAAGAGGGAGAAAGCCGTC-3′ (SEQ ID NO: 5539)5′-GUCAGCAAGAGGGAGAAAGCCGUct-3′ (SEQ ID NO: 1512)3′-UGCAGUCGUUCUCCCUCUUUCGGCAGA-5′ (SEQ ID NO: 3526) LDHA-592 Target:5′-ACGTCAGCAAGAGGGAGAAAGCCGTCT-3′ (SEQ ID NO: 5540)5′-UCAGCAAGAGGGAGAAAGCCGUCtt-3′ (SEQ ID NO: 1513)3′-GCAGUCGUUCUCCCUCUUUCGGCAGAA-5′ (SEQ ID NO: 3527) LDHA-593 Target:5′-CGTCAGCAAGAGGGAGAAAGCCGTCTT-3′ (SEQ ID NO: 5541)5′-CAGCAAGAGGGAGAAAGCCGUCUta-3′ (SEQ ID NO: 1514)3′-CAGUCGUUCUCCCUCUUUCGGCAGAAU-5′ (SEQ ID NO: 3528) LDHA-594 Target:5′-GTCAGCAAGAGGGAGAAAGCCGTCTTA-3′ (SEQ ID NO: 5542)5′-AGCAAGAGGGAGAAAGCCGUCUUaa-3′ (SEQ ID NO: 1515)3′-AGUCGUUCUCCCUCUUUCGGCAGAAUU-5′ (SEQ ID NO: 3529) LDHA-595 Target:5′-TCAGCAAGAGGGAGAAAGCCGTCTTAA-3′ (SEQ ID NO: 5543)5′-GCAAGAGGGAGAAAGCCGUCUUAat-3′ (SEQ ID NO: 1516)3′-GUCGUUCUCCCUCUUUCGGCAGAAUUA-5′ (SEQ ID NO: 3530) LDHA-596 Target:5′-CAGCAAGAGGGAGAAAGCCGTCTTAAT-3′ (SEQ ID NO: 5544)5′-CAAGAGGGAGAAAGCCGUCUUAAtt-3′ (SEQ ID NO: 1517)3′-UCGUUCUCCCUCUUUCGGCAGAAUUAA-5′ (SEQ ID NO: 3531) LDHA-597 Target:5′-AGCAAGAGGGAGAAAGCCGTCTTAATT-3′ (SEQ ID NO: 5545)5′-AAGAGGGAGAAAGCCGUCUUAAUtt-3′ (SEQ ID NO: 1518)3′-CGUUCUCCCUCUUUCGGCAGAAUUAAA-5′ (SEQ ID NO: 3532) LDHA-598 Target:5′-GCAAGAGGGAGAAAGCCGTCTTAATTT-3′ (SEQ ID NO: 5546)5′-AGAGGGAGAAAGCCGUCUUAAUUtg-3′ (SEQ ID NO: 1519)3′-GUUCUCCCUCUUUCGGCAGAAUUAAAC-5′ (SEQ ID NO: 3533) LDHA-599 Target:5′-CAAGAGGGAGAAAGCCGTCTTAATTTG-3′ (SEQ ID NO: 5547)5′-GAGGGAGAAAGCCGUCUUAAUUUgg-3′ (SEQ ID NO: 1520)3′-UUCUCCCUCUUUCGGCAGAAUUAAACC-5′ (SEQ ID NO: 3534) LDHA-600 Target:5′-AAGAGGGAGAAAGCCGTCTTAATTTGG-3′ (SEQ ID NO: 5548)5′-AGGGAGAAAGCCGUCUUAAUUUGgt-3′ (SEQ ID NO: 1521)3′-UCUCCCUCUUUCGGCAGAAUUAAACCA-5′ (SEQ ID NO: 3535) LDHA-601 Target:5′-AGAGGGAGAAAGCCGTCTTAATTTGGT-3′ (SEQ ID NO: 5549)5′-GGGAGAAAGCCGUCUUAAUUUGGtc-3′ (SEQ ID NO: 1522)3′-CUCCCUCUUUCGGCAGAAUUAAACCAG-5′ (SEQ ID NO: 3536) LDHA-602 Target:5′-GAGGGAGAAAGCCGTCTTAATTTGGTC-3′ (SEQ ID NO: 5550)5′-GGAGAAAGCCGUCUUAAUUUGGUcc-3′ (SEQ ID NO: 1523)3′-UCCCUCUUUCGGCAGAAUUAAACCAGG-5′ (SEQ ID NO: 3537) LDHA-603 Target:5′-AGGGAGAAAGCCGTCTTAATTTGGTCC-3′ (SEQ ID NO: 5551)5′-GAGAAAGCCGUCUUAAUUUGGUCca-3′ (SEQ ID NO: 1524)3′-CCCUCUUUCGGCAGAAUUAAACCAGGU-5′ (SEQ ID NO: 3538) LDHA-604 Target:5′-GGGAGAAAGCCGTCTTAATTTGGTCCA-3′ (SEQ ID NO: 5552)5′-AGAAAGCCGUCUUAAUUUGGUCCag-3′ (SEQ ID NO: 1525)3′-CCUCUUUCGGCAGAAUUAAACCAGGUC-5′ (SEQ ID NO: 3539) LDHA-605 Target:5′-GGAGAAAGCCGTCTTAATTTGGTCCAG-3′ (SEQ ID NO: 5553)5′-GAAAGCCGUCUUAAUUUGGUCCAgc-3′ (SEQ ID NO: 1526)3′-CUCUUUCGGCAGAAUUAAACCAGGUCG-5′ (SEQ ID NO: 3540) LDHA-606 Target:5′-GAGAAAGCCGTCTTAATTTGGTCCAGC-3′ (SEQ ID NO: 5554)5′-AAAGCCGUCUUAAUUUGGUCCAGcg-3′ (SEQ ID NO: 1527)3′-UCUUUCGGCAGAAUUAAACCAGGUCGC-5′ (SEQ ID NO: 3541) LDHA-607 Target:5′-AGAAAGCCGTCTTAATTTGGTCCAGCG-3′ (SEQ ID NO: 5555)5′-AAGCCGUCUUAAUUUGGUCCAGCgt-3′ (SEQ ID NO: 1528)3′-CUUUCGGCAGAAUUAAACCAGGUCGCA-5′ (SEQ ID NO: 3542) LDHA-608 Target:5′-GAAAGCCGTCTTAATTTGGTCCAGCGT-3′ (SEQ ID NO: 5556)5′-AGCCGUCUUAAUUUGGUCCAGCGta-3′ (SEQ ID NO: 1529)3′-UUUCGGCAGAAUUAAACCAGGUCGCAU-5′ (SEQ ID NO: 3543) LDHA-609 Target:5′-AAAGCCGTCTTAATTTGGTCCAGCGTA-3′ (SEQ ID NO: 5557)5′-GCCGUCUUAAUUUGGUCCAGCGUaa-3′ (SEQ ID NO: 1530)3′-UUCGGCAGAAUUAAACCAGGUCGCAUU-5′ (SEQ ID NO: 3544) LDHA-610 Target:5′-AAGCCGTCTTAATTTGGTCCAGCGTAA-3′ (SEQ ID NO: 5558)5′-CCGUCUUAAUUUGGUCCAGCGUAac-3′ (SEQ ID NO: 1531)3′-UCGGCAGAAUUAAACCAGGUCGCAUUG-5′ (SEQ ID NO: 3545) LDHA-611 Target:5′-AGCCGTCTTAATTTGGTCCAGCGTAAC-3′ (SEQ ID NO: 5559)5′-CGUCUUAAUUUGGUCCAGCGUAAcg-3′ (SEQ ID NO: 1532)3′-CGGCAGAAUUAAACCAGGUCGCAUUGC-5′ (SEQ ID NO: 3546) LDHA-612 Target:5′-GCCGTCTTAATTTGGTCCAGCGTAACG-3′ (SEQ ID NO: 5560)5′-GUCUUAAUUUGGUCCAGCGUAACgt-3′ (SEQ ID NO: 1533)3′-GGCAGAAUUAAACCAGGUCGCAUUGCA-5′ (SEQ ID NO: 3547) LDHA-613 Target:5′-CCGTCTTAATTTGGTCCAGCGTAACGT-3′ (SEQ ID NO: 5561)5′-UCUUAAUUUGGUCCAGCGUAACGtg-3′ (SEQ ID NO: 1534)3′-GCAGAAUUAAACCAGGUCGCAUUGCAC-5′ (SEQ ID NO: 3548) LDHA-614 Target:5′-CGTCTTAATTTGGTCCAGCGTAACGTG-3′ (SEQ ID NO: 5562)5′-CUUAAUUUGGUCCAGCGUAACGUga-3′ (SEQ ID NO: 1535)3′-CAGAAUUAAACCAGGUCGCAUUGCACU-5′ (SEQ ID NO: 3549) LDHA-615 Target:5′-GTCTTAATTTGGTCCAGCGTAACGTGA-3′ (SEQ ID NO: 5563)5′-UUAAUUUGGUCCAGCGUAACGUGaa-3′ (SEQ ID NO: 1536)3′-AGAAUUAAACCAGGUCGCAUUGCACUU-5′ (SEQ ID NO: 3550) LDHA-616 Target:5′-TCTTAATTTGGTCCAGCGTAACGTGAA-3′ (SEQ ID NO: 5564)5′-UAAUUUGGUCCAGCGUAACGUGAac-3′ (SEQ ID NO: 1537)3′-GAAUUAAACCAGGUCGCAUUGCACUUG-5′ (SEQ ID NO: 3551) LDHA-617 Target:5′-CTTAATTTGGTCCAGCGTAACGTGAAC-3′ (SEQ ID NO: 5565)5′-AAUUUGGUCCAGCGUAACGUGAAca-3′ (SEQ ID NO: 1538)3′-AAUUAAACCAGGUCGCAUUGCACUUGU-5′ (SEQ ID NO: 3552) LDHA-618 Target:5′-TTAATTTGGTCCAGCGTAACGTGAACA-3′ (SEQ ID NO: 5566)5′-AUUUGGUCCAGCGUAACGUGAACat-3′ (SEQ ID NO: 1539)3′-AUUAAACCAGGUCGCAUUGCACUUGUA-5′ (SEQ ID NO: 3553) LDHA-619 Target:5′-TAATTTGGTCCAGCGTAACGTGAACAT-3′ (SEQ ID NO: 5567)5′-UUUGGUCCAGCGUAACGUGAACAtc-3′ (SEQ ID NO: 1540)3′-UUAAACCAGGUCGCAUUGCACUUGUAG-5′ (SEQ ID NO: 3554) LDHA-620 Target:5′-AATTTGGTCCAGCGTAACGTGAACATC-3′ (SEQ ID NO: 5568)5′-UUGGUCCAGCGUAACGUGAACAUct-3′ (SEQ ID NO: 1541)3′-UAAACCAGGUCGCAUUGCACUUGUAGA-5′ (SEQ ID NO: 3555) LDHA-621 Target:5′-ATTTGGTCCAGCGTAACGTGAACATCT-3′ (SEQ ID NO: 5569)5′-UGGUCCAGCGUAACGUGAACAUCtt-3′ (SEQ ID NO: 1542)3′-AAACCAGGUCGCAUUGCACUUGUAGAA-5′ (SEQ ID NO: 3556) LDHA-622 Target:5′-TTTGGTCCAGCGTAACGTGAACATCTT-3′ (SEQ ID NO: 5570)5′-GGUCCAGCGUAACGUGAACAUCUtt-3′ (SEQ ID NO: 1543)3′-AACCAGGUCGCAUUGCACUUGUAGAAA-5′ (SEQ ID NO: 3557) LDHA-623 Target:5′-TTGGTCCAGCGTAACGTGAACATCTTT-3′ (SEQ ID NO: 5571)5′-GUCCAGCGUAACGUGAACAUCUUta-3′ (SEQ ID NO: 1544)3′-ACCAGGUCGCAUUGCACUUGUAGAAAU-5′ (SEQ ID NO: 3558) LDHA-624 Target:5′-TGGTCCAGCGTAACGTGAACATCTTTA-3′ (SEQ ID NO: 5572)5′-UCCAGCGUAACGUGAACAUCUUUaa-3′ (SEQ ID NO: 1545)3′-CCAGGUCGCAUUGCACUUGUAGAAAUU-5′ (SEQ ID NO: 3559) LDHA-625 Target:5′-GGTCCAGCGTAACGTGAACATCTTTAA-3′ (SEQ ID NO: 5573)5′-CCAGCGUAACGUGAACAUCUUUAaa-3′ (SEQ ID NO: 1546)3′-CAGGUCGCAUUGCACUUGUAGAAAUUU-5′ (SEQ ID NO: 3560) LDHA-626 Target:5′-GTCCAGCGTAACGTGAACATCTTTAAA-3′ (SEQ ID NO: 5574)5′-CAGCGUAACGUGAACAUCUUUAAat-3′ (SEQ ID NO: 1547)3′-AGGUCGCAUUGCACUUGUAGAAAUUUA-5′ (SEQ ID NO: 3561) LDHA-627 Target:5′-TCCAGCGTAACGTGAACATCTTTAAAT-3′ (SEQ ID NO: 5575)5′-AGCGUAACGUGAACAUCUUUAAAtt-3′ (SEQ ID NO: 1548)3′-GGUCGCAUUGCACUUGUAGAAAUUUAA-5′ (SEQ ID NO: 3562) LDHA-628 Target:5′-CCAGCGTAACGTGAACATCTTTAAATT-3′ (SEQ ID NO: 5576)5′-GCGUAACGUGAACAUCUUUAAAUtc-3′ (SEQ ID NO: 1549)3′-GUCGCAUUGCACUUGUAGAAAUUUAAG-5′ (SEQ ID NO: 3563) LDHA-629 Target:5′-CAGCGTAACGTGAACATCTTTAAATTC-3′ (SEQ ID NO: 5577)5′-CGUAACGUGAACAUCUUUAAAUUca-3′ (SEQ ID NO: 1550)3′-UCGCAUUGCACUUGUAGAAAUUUAAGU-5′ (SEQ ID NO: 3564) LDHA-630 Target:5′-AGCGTAACGTGAACATCTTTAAATTCA-3′ (SEQ ID NO: 5578)5′-GUAACGUGAACAUCUUUAAAUUCat-3′ (SEQ ID NO: 1551)3′-CGCAUUGCACUUGUAGAAAUUUAAGUA-5′ (SEQ ID NO: 3565) LDHA-631 Target:5′-GCGTAACGTGAACATCTTTAAATTCAT-3′ (SEQ ID NO: 5579)5′-UAACGUGAACAUCUUUAAAUUCAtc-3′ (SEQ ID NO: 1552)3′-GCAUUGCACUUGUAGAAAUUUAAGUAG-5′ (SEQ ID NO: 3566) LDHA-632 Target:5′-CGTAACGTGAACATCTTTAAATTCATC-3′ (SEQ ID NO: 5580)5′-AACGUGAACAUCUUUAAAUUCAUca-3′ (SEQ ID NO: 1553)3′-CAUUGCACUUGUAGAAAUUUAAGUAGU-5′ (SEQ ID NO: 3567) LDHA-633 Target:5′-GTAACGTGAACATCTTTAAATTCATCA-3′ (SEQ ID NO: 5581)5′-ACGUGAACAUCUUUAAAUUCAUCat-3′ (SEQ ID NO: 1554)3′-AUUGCACUUGUAGAAAUUUAAGUAGUA-5′ (SEQ ID NO: 3568) LDHA-634 Target:5′-TAACGTGAACATCTTTAAATTCATCAT-3′ (SEQ ID NO: 5582)5′-CGUGAACAUCUUUAAAUUCAUCAtt-3′ (SEQ ID NO: 1555)3′-UUGCACUUGUAGAAAUUUAAGUAGUAA-5′ (SEQ ID NO: 3569) LDHA-635 Target:5′-AACGTGAACATCTTTAAATTCATCATT-3′ (SEQ ID NO: 5583)5′-GUGAACAUCUUUAAAUUCAUCAUtc-3′ (SEQ ID NO: 1556)3′-UGCACUUGUAGAAAUUUAAGUAGUAAG-5′ (SEQ ID NO: 3570) LDHA-636 Target:5′-ACGTGAACATCTTTAAATTCATCATTC-3′ (SEQ ID NO: 5584)5′-UGAACAUCUUUAAAUUCAUCAUUcc-3′ (SEQ ID NO: 1557)3′-GCACUUGUAGAAAUUUAAGUAGUAAGG-5′ (SEQ ID NO: 3571) LDHA-637 Target:5′-CGTGAACATCTTTAAATTCATCATTCC-3′ (SEQ ID NO: 5585)5′-GAACAUCUUUAAAUUCAUCAUUCct-3′ (SEQ ID NO: 1558)3′-CACUUGUAGAAAUUUAAGUAGUAAGGA-5′ (SEQ ID NO: 3572) LDHA-638 Target:5′-GTGAACATCTTTAAATTCATCATTCCT-3′ (SEQ ID NO: 5586)5′-AACAUCUUUAAAUUCAUCAUUCCta-3′ (SEQ ID NO: 1559)3′-ACUUGUAGAAAUUUAAGUAGUAAGGAU-5′ (SEQ ID NO: 3573) LDHA-639 Target:5′-TGAACATCTTTAAATTCATCATTCCTA-3′ (SEQ ID NO: 5587)5′-ACAUCUUUAAAUUCAUCAUUCCUaa-3′ (SEQ ID NO: 1560)3′-CUUGUAGAAAUUUAAGUAGUAAGGAUU-5′ (SEQ ID NO: 3574) LDHA-640 Target:5′-GAACATCTTTAAATTCATCATTCCTAA-3′ (SEQ ID NO: 5588)5′-CAUCUUUAAAUUCAUCAUUCCUAat-3′ (SEQ ID NO: 1561)3′-UUGUAGAAAUUUAAGUAGUAAGGAUUA-5′ (SEQ ID NO: 3575) LDHA-641 Target:5′-AACATCTTTAAATTCATCATTCCTAAT-3′ (SEQ ID NO: 5589)5′-AUCUUUAAAUUCAUCAUUCCUAAtg-3′ (SEQ ID NO: 1562)3′-UGUAGAAAUUUAAGUAGUAAGGAUUAC-5′ (SEQ ID NO: 3576) LDHA-642 Target:5′-ACATCTTTAAATTCATCATTCCTAATG-3′ (SEQ ID NO: 5590)5′-UCUUUAAAUUCAUCAUUCCUAAUgt-3′ (SEQ ID NO: 1563)3′-GUAGAAAUUUAAGUAGUAAGGAUUACA-5′ (SEQ ID NO: 3577) LDHA-643 Target:5′-CATCTTTAAATTCATCATTCCTAATGT-3′ (SEQ ID NO: 5591)5′-CUUUAAAUUCAUCAUUCCUAAUGtt-3′ (SEQ ID NO: 1564)3′-UAGAAAUUUAAGUAGUAAGGAUUACAA-5′ (SEQ ID NO: 3578) LDHA-644 Target:5′-ATCTTTAAATTCATCATTCCTAATGTT-3′ (SEQ ID NO: 5592)5′-UUUAAAUUCAUCAUUCCUAAUGUtg-3′ (SEQ ID NO: 1565)3′-AGAAAUUUAAGUAGUAAGGAUUACAAC-5′ (SEQ ID NO: 3579) LDHA-645 Target:5′-TCTTTAAATTCATCATTCCTAATGTTG-3′ (SEQ ID NO: 5593)5′-UUAAAUUCAUCAUUCCUAAUGUUgt-3′ (SEQ ID NO: 1566)3′-GAAAUUUAAGUAGUAAGGAUUACAACA-5′ (SEQ ID NO: 3580) LDHA-646 Target:5′-CTTTAAATTCATCATTCCTAATGTTGT-3′ (SEQ ID NO: 5594)5′-UAAAUUCAUCAUUCCUAAUGUUGta-3′ (SEQ ID NO: 1567)3′-AAAUUUAAGUAGUAAGGAUUACAACAU-5′ (SEQ ID NO: 3581) LDHA-647 Target:5′-TTTAAATTCATCATTCCTAATGTTGTA-3′ (SEQ ID NO: 5595)5′-AAAUUCAUCAUUCCUAAUGUUGUaa-3′ (SEQ ID NO: 1568)3′-AAUUUAAGUAGUAAGGAUUACAACAUU-5′ (SEQ ID NO: 3582) LDHA-648 Target:5′-TTAAATTCATCATTCCTAATGTTGTAA-3′ (SEQ ID NO: 5596)5′-AAUUCAUCAUUCCUAAUGUUGUAaa-3′ (SEQ ID NO: 1569)3′-AUUUAAGUAGUAAGGAUUACAACAUUU-5′ (SEQ ID NO: 3583) LDHA-649 Target:5′-TAAATTCATCATTCCTAATGTTGTAAA-3′ (SEQ ID NO: 5597)5′-AUUCAUCAUUCCUAAUGUUGUAAaa-3′ (SEQ ID NO: 1570)3′-UUUAAGUAGUAAGGAUUACAACAUUUU-5′ (SEQ ID NO: 3584) LDHA-650 Target:5′-AAATTCATCATTCCTAATGTTGTAAAA-3′ (SEQ ID NO: 5598)5′-UUCAUCAUUCCUAAUGUUGUAAAat-3′ (SEQ ID NO: 1571)3′-UUAAGUAGUAAGGAUUACAACAUUUUA-5′ (SEQ ID NO: 3585) LDHA-651 Target:5′-AATTCATCATTCCTAATGTTGTAAAAT-3′ (SEQ ID NO: 5599)5′-UCAUCAUUCCUAAUGUUGUAAAAta-3′ (SEQ ID NO: 1572)3′-UAAGUAGUAAGGAUUACAACAUUUUAU-5′ (SEQ ID NO: 3586) LDHA-652 Target:5′-ATTCATCATTCCTAATGTTGTAAAATA-3′ (SEQ ID NO: 5600)5′-CAUCAUUCCUAAUGUUGUAAAAUac-3′ (SEQ ID NO: 1573)3′-AAGUAGUAAGGAUUACAACAUUUUAUG-5′ (SEQ ID NO: 3587) LDHA-653 Target:5′-TTCATCATTCCTAATGTTGTAAAATAC-3′ (SEQ ID NO: 5601)5′-AUCAUUCCUAAUGUUGUAAAAUAca-3′ (SEQ ID NO: 1574)3′-AGUAGUAAGGAUUACAACAUUUUAUGU-5′ (SEQ ID NO: 3588) LDHA-654 Target:5′-TCATCATTCCTAATGTTGTAAAATACA-3′ (SEQ ID NO: 5602)5′-UCAUUCCUAAUGUUGUAAAAUACag-3′ (SEQ ID NO: 1575)3′-GUAGUAAGGAUUACAACAUUUUAUGUC-5′ (SEQ ID NO: 3589) LDHA-655 Target:5′-CATCATTCCTAATGTTGTAAAATACAG-3′ (SEQ ID NO: 5603)5′-CAUUCCUAAUGUUGUAAAAUACAgc-3′ (SEQ ID NO: 1576)3′-UAGUAAGGAUUACAACAUUUUAUGUCG-5′ (SEQ ID NO: 3590) LDHA-656 Target:5′-ATCATTCCTAATGTTGTAAAATACAGC-3′ (SEQ ID NO: 5604)5′-AUUCCUAAUGUUGUAAAAUACAGcc-3′ (SEQ ID NO: 1577)3′-AGUAAGGAUUACAACAUUUUAUGUCGG-5′ (SEQ ID NO: 3591) LDHA-657 Target:5′-TCATTCCTAATGTTGTAAAATACAGCC-3′ (SEQ ID NO: 5605)5′-UUCCUAAUGUUGUAAAAUACAGCcc-3′ (SEQ ID NO: 1578)3′-GUAAGGAUUACAACAUUUUAUGUCGGG-5′ (SEQ ID NO: 3592) LDHA-658 Target:5′-CATTCCTAATGTTGTAAAATACAGCCC-3′ (SEQ ID NO: 5606)5′-UCCUAAUGUUGUAAAAUACAGCCcg-3′ (SEQ ID NO: 1579)3′-UAAGGAUUACAACAUUUUAUGUCGGGC-5′ (SEQ ID NO: 3593) LDHA-659 Target:5′-ATTCCTAATGTTGTAAAATACAGCCCG-3′ (SEQ ID NO: 5607)5′-CCUAAUGUUGUAAAAUACAGCCCga-3′ (SEQ ID NO: 1580)3′-AAGGAUUACAACAUUUUAUGUCGGGCU-5′ (SEQ ID NO: 3594) LDHA-660 Target:5′-TTCCTAATGTTGTAAAATACAGCCCGA-3′ (SEQ ID NO: 5608)5′-CUAAUGUUGUAAAAUACAGCCCGaa-3′ (SEQ ID NO: 1581)3′-AGGAUUACAACAUUUUAUGUCGGGCUU-5′ (SEQ ID NO: 3595) LDHA-661 Target:5′-TCCTAATGTTGTAAAATACAGCCCGAA-3′ (SEQ ID NO: 5609)5′-UAAUGUUGUAAAAUACAGCCCGAac-3′ (SEQ ID NO: 1582)3′-GGAUUACAACAUUUUAUGUCGGGCUUG-5′ (SEQ ID NO: 3596) LDHA-662 Target:5′-CCTAATGTTGTAAAATACAGCCCGAAC-3′ (SEQ ID NO: 5610)5′-AAUGUUGUAAAAUACAGCCCGAAct-3′ (SEQ ID NO: 1583)3′-GAUUACAACAUUUUAUGUCGGGCUUGA-5′ (SEQ ID NO: 3597) LDHA-663 Target:5′-CTAATGTTGTAAAATACAGCCCGAACT-3′ (SEQ ID NO: 5611)5′-AUGUUGUAAAAUACAGCCCGAACtg-3′ (SEQ ID NO: 1584)3′-AUUACAACAUUUUAUGUCGGGCUUGAC-5′ (SEQ ID NO: 3598) LDHA-664 Target:5′-TAATGTTGTAAAATACAGCCCGAACTG-3′ (SEQ ID NO: 5612)5′-UGUUGUAAAAUACAGCCCGAACUgc-3′ (SEQ ID NO: 1585)3′-UUACAACAUUUUAUGUCGGGCUUGACG-5′ (SEQ ID NO: 3599) LDHA-665 Target:5′-AATGTTGTAAAATACAGCCCGAACTGC-3′ (SEQ ID NO: 5613)5′-GUUGUAAAAUACAGCCCGAACUGca-3′ (SEQ ID NO: 1586)3′-UACAACAUUUUAUGUCGGGCUUGACGU-5′ (SEQ ID NO: 3600) LDHA-666 Target:5′-ATGTTGTAAAATACAGCCCGAACTGCA-3′ (SEQ ID NO: 5614)5′-UUGUAAAAUACAGCCCGAACUGCaa-3′ (SEQ ID NO: 1587)3′-ACAACAUUUUAUGUCGGGCUUGACGUU-5′ (SEQ ID NO: 3601) LDHA-667 Target:5′-TGTTGTAAAATACAGCCCGAACTGCAA-3′ (SEQ ID NO: 5615)5′-UGUAAAAUACAGCCCGAACUGCAag-3′ (SEQ ID NO: 1588)3′-CAACAUUUUAUGUCGGGCUUGACGUUC-5′ (SEQ ID NO: 3602) LDHA-668 Target:5′-GTTGTAAAATACAGCCCGAACTGCAAG-3′ (SEQ ID NO: 5616)5′-GUAAAAUACAGCCCGAACUGCAAgt-3′ (SEQ ID NO: 1589)3′-AACAUUUUAUGUCGGGCUUGACGUUCA-5′ (SEQ ID NO: 3603) LDHA-669 Target:5′-TTGTAAAATACAGCCCGAACTGCAAGT-3′ (SEQ ID NO: 5617)5′-UAAAAUACAGCCCGAACUGCAAGtt-3′ (SEQ ID NO: 1590)3′-ACAUUUUAUGUCGGGCUUGACGUUCAA-5′ (SEQ ID NO: 3604) LDHA-670 Target:5′-TGTAAAATACAGCCCGAACTGCAAGTT-3′ (SEQ ID NO: 5618)5′-AAAAUACAGCCCGAACUGCAAGUtg-3′ (SEQ ID NO: 1591)3′-CAUUUUAUGUCGGGCUUGACGUUCAAC-5′ (SEQ ID NO: 3605) LDHA-671 Target:5′-GTAAAATACAGCCCGAACTGCAAGTTG-3′ (SEQ ID NO: 5619)5′-AAAUACAGCCCGAACUGCAAGUUgc-3′ (SEQ ID NO: 1592)3′-AUUUUAUGUCGGGCUUGACGUUCAACG-5′ (SEQ ID NO: 3606) LDHA-672 Target:5′-TAAAATACAGCCCGAACTGCAAGTTGC-3′ (SEQ ID NO: 5620)5′-AAUACAGCCCGAACUGCAAGUUGct-3′ (SEQ ID NO: 1593)3′-UUUUAUGUCGGGCUUGACGUUCAACGA-5′ (SEQ ID NO: 3607) LDHA-673 Target:5′-AAAATACAGCCCGAACTGCAAGTTGCT-3′ (SEQ ID NO: 5621)5′-AUACAGCCCGAACUGCAAGUUGCtt-3′ (SEQ ID NO: 1594)3′-UUUAUGUCGGGCUUGACGUUCAACGAA-5′ (SEQ ID NO: 3608) LDHA-674 Target:5′-AAATACAGCCCGAACTGCAAGTTGCTT-3′ (SEQ ID NO: 5622)5′-UACAGCCCGAACUGCAAGUUGCUta-3′ (SEQ ID NO: 1595)3′-UUAUGUCGGGCUUGACGUUCAACGAAU-5′ (SEQ ID NO: 3609) LDHA-675 Target:5′-AATACAGCCCGAACTGCAAGTTGCTTA-3′ (SEQ ID NO: 5623)5′-ACAGCCCGAACUGCAAGUUGCUUat-3′ (SEQ ID NO: 1596)3′-UAUGUCGGGCUUGACGUUCAACGAAUA-5′ (SEQ ID NO: 3610) LDHA-676 Target:5′-ATACAGCCCGAACTGCAAGTTGCTTAT-3′ (SEQ ID NO: 5624)5′-CAGCCCGAACUGCAAGUUGCUUAtt-3′ (SEQ ID NO: 1597)3′-AUGUCGGGCUUGACGUUCAACGAAUAA-5′ (SEQ ID NO: 3611) LDHA-677 Target:5′-TACAGCCCGAACTGCAAGTTGCTTATT-3′ (SEQ ID NO: 5625)5′-AGCCCGAACUGCAAGUUGCUUAUtg-3′ (SEQ ID NO: 1598)3′-UGUCGGGCUUGACGUUCAACGAAUAAC-5′ (SEQ ID NO: 3612) LDHA-678 Target:5′-ACAGCCCGAACTGCAAGTTGCTTATTG-3′ (SEQ ID NO: 5626)5′-GCCCGAACUGCAAGUUGCUUAUUgt-3′ (SEQ ID NO: 1599)3′-GUCGGGCUUGACGUUCAACGAAUAACA-5′ (SEQ ID NO: 3613) LDHA-679 Target:5′-CAGCCCGAACTGCAAGTTGCTTATTGT-3′ (SEQ ID NO: 5627)5′-CCCGAACUGCAAGUUGCUUAUUGtt-3′ (SEQ ID NO: 1600)3′-UCGGGCUUGACGUUCAACGAAUAACAA-5′ (SEQ ID NO: 3614) LDHA-680 Target:5′-AGCCCGAACTGCAAGTTGCTTATTGTT-3′ (SEQ ID NO: 5628)5′-CCGAACUGCAAGUUGCUUAUUGUtt-3′ (SEQ ID NO: 1601)3′-CGGGCUUGACGUUCAACGAAUAACAAA-5′ (SEQ ID NO: 3615) LDHA-681 Target:5′-GCCCGAACTGCAAGTTGCTTATTGTTT-3′ (SEQ ID NO: 5629)5′-CGAACUGCAAGUUGCUUAUUGUUtc-3′ (SEQ ID NO: 1602)3′-GGGCUUGACGUUCAACGAAUAACAAAG-5′ (SEQ ID NO: 3616) LDHA-682 Target:5′-CCCGAACTGCAAGTTGCTTATTGTTTC-3′ (SEQ ID NO: 5630)5′-GAACUGCAAGUUGCUUAUUGUUUca-3′ (SEQ ID NO: 1603)3′-GGCUUGACGUUCAACGAAUAACAAAGU-5′ (SEQ ID NO: 3617) LDHA-683 Target:5′-CCGAACTGCAAGTTGCTTATTGTTTCA-3′ (SEQ ID NO: 5631)5′-AACUGCAAGUUGCUUAUUGUUUCaa-3′ (SEQ ID NO: 1604)3′-GCUUGACGUUCAACGAAUAACAAAGUU-5′ (SEQ ID NO: 3618) LDHA-684 Target:5′-CGAACTGCAAGTTGCTTATTGTTTCAA-3′ (SEQ ID NO: 5632)5′-ACUGCAAGUUGCUUAUUGUUUCAaa-3′ (SEQ ID NO: 1605)3′-CUUGACGUUCAACGAAUAACAAAGUUU-5′ (SEQ ID NO: 3619) LDHA-685 Target:5′-GAACTGCAAGTTGCTTATTGTTTCAAA-3′ (SEQ ID NO: 5633)5′-CUGCAAGUUGCUUAUUGUUUCAAat-3′ (SEQ ID NO: 1606)3′-UUGACGUUCAACGAAUAACAAAGUUUA-5′ (SEQ ID NO: 3620) LDHA-686 Target:5′-AACTGCAAGTTGCTTATTGTTTCAAAT-3′ (SEQ ID NO: 5634)5′-UGCAAGUUGCUUAUUGUUUCAAAtc-3′ (SEQ ID NO: 1607)3′-UGACGUUCAACGAAUAACAAAGUUUAG-5′ (SEQ ID NO: 3621) LDHA-687 Target:5′-ACTGCAAGTTGCTTATTGTTTCAAATC-3′ (SEQ ID NO: 5635)5′-GCAAGUUGCUUAUUGUUUCAAAUcc-3′ (SEQ ID NO: 1608)3′-GACGUUCAACGAAUAACAAAGUUUAGG-5′ (SEQ ID NO: 3622) LDHA-688 Target:5′-CTGCAAGTTGCTTATTGTTTCAAATCC-3′ (SEQ ID NO: 5636)5′-CAAGUUGCUUAUUGUUUCAAAUCca-3′ (SEQ ID NO: 1609)3′-ACGUUCAACGAAUAACAAAGUUUAGGU-5′ (SEQ ID NO: 3623) LDHA-689 Target:5′-TGCAAGTTGCTTATTGTTTCAAATCCA-3′ (SEQ ID NO: 5637)5′-AAGUUGCUUAUUGUUUCAAAUCCag-3′ (SEQ ID NO: 1610)3′-CGUUCAACGAAUAACAAAGUUUAGGUC-5′ (SEQ ID NO: 3624) LDHA-690 Target:5′-GCAAGTTGCTTATTGTTTCAAATCCAG-3′ (SEQ ID NO: 5638)5′-AGUUGCUUAUUGUUUCAAAUCCAgt-3′ (SEQ ID NO: 1611)3′-GUUCAACGAAUAACAAAGUUUAGGUCA-5′ (SEQ ID NO: 3625) LDHA-691 Target:5′-CAAGTTGCTTATTGTTTCAAATCCAGT-3′ (SEQ ID NO: 5639)5′-GUUGCUUAUUGUUUCAAAUCCAGtg-3′ (SEQ ID NO: 1612)3′-UUCAACGAAUAACAAAGUUUAGGUCAC-5′ (SEQ ID NO: 3626) LDHA-692 Target:5′-AAGTTGCTTATTGTTTCAAATCCAGTG-3′ (SEQ ID NO: 5640)5′-UUGCUUAUUGUUUCAAAUCCAGUgg-3′ (SEQ ID NO: 1613)3′-UCAACGAAUAACAAAGUUUAGGUCACC-5′ (SEQ ID NO: 3627) LDHA-693 Target:5′-AGTTGCTTATTGTTTCAAATCCAGTGG-3′ (SEQ ID NO: 5641)5′-UGCUUAUUGUUUCAAAUCCAGUGga-3′ (SEQ ID NO: 1614)3′-CAACGAAUAACAAAGUUUAGGUCACCU-5′ (SEQ ID NO: 3628) LDHA-694 Target:5′-GTTGCTTATTGTTTCAAATCCAGTGGA-3′ (SEQ ID NO: 5642)5′-GCUUAUUGUUUCAAAUCCAGUGGat-3′ (SEQ ID NO: 1615)3′-AACGAAUAACAAAGUUUAGGUCACCUA-5′ (SEQ ID NO: 3629) LDHA-695 Target:5′-TTGCTTATTGTTTCAAATCCAGTGGAT-3′ (SEQ ID NO: 5643)5′-CUUAUUGUUUCAAAUCCAGUGGAta-3′ (SEQ ID NO: 1616)3′-ACGAAUAACAAAGUUUAGGUCACCUAU-5′ (SEQ ID NO: 3630) LDHA-696 Target:5′-TGCTTATTGTTTCAAATCCAGTGGATA-3′ (SEQ ID NO: 5644)5′-UUAUUGUUUCAAAUCCAGUGGAUat-3′ (SEQ ID NO: 1617)3′-CGAAUAACAAAGUUUAGGUCACCUAUA-5′ (SEQ ID NO: 3631) LDHA-697 Target:5′-GCTTATTGTTTCAAATCCAGTGGATAT-3′ (SEQ ID NO: 5645)5′-UAUUGUUUCAAAUCCAGUGGAUAtc-3′ (SEQ ID NO: 1618)3′-GAAUAACAAAGUUUAGGUCACCUAUAG-5′ (SEQ ID NO: 3632) LDHA-698 Target:5′-CTTATTGTTTCAAATCCAGTGGATATC-3′ (SEQ ID NO: 5646)5′-AUUGUUUCAAAUCCAGUGGAUAUct-3′ (SEQ ID NO: 1619)3′-AAUAACAAAGUUUAGGUCACCUAUAGA-5′ (SEQ ID NO: 3633) LDHA-699 Target:5′-TTATTGTTTCAAATCCAGTGGATATCT-3′ (SEQ ID NO: 5647)5′-UUGUUUCAAAUCCAGUGGAUAUCtt-3′ (SEQ ID NO: 1620)3′-AUAACAAAGUUUAGGUCACCUAUAGAA-5′ (SEQ ID NO: 3634) LDHA-700 Target:5′-TATTGTTTCAAATCCAGTGGATATCTT-3′ (SEQ ID NO: 5648)5′-UGUUUCAAAUCCAGUGGAUAUCUtg-3′ (SEQ ID NO: 1621)3′-UAACAAAGUUUAGGUCACCUAUAGAAC-5′ (SEQ ID NO: 3635) LDHA-701 Target:5′-ATTGTTTCAAATCCAGTGGATATCTTG-3′ (SEQ ID NO: 5649)5′-GUUUCAAAUCCAGUGGAUAUCUUga-3′ (SEQ ID NO: 1622)3′-AACAAAGUUUAGGUCACCUAUAGAACU-5′ (SEQ ID NO: 3636) LDHA-702 Target:5′-TTGTTTCAAATCCAGTGGATATCTTGA-3′ (SEQ ID NO: 5650)5′-UUUCAAAUCCAGUGGAUAUCUUGac-3′ (SEQ ID NO: 1623)3′-ACAAAGUUUAGGUCACCUAUAGAACUG-5′ (SEQ ID NO: 3637) LDHA-703 Target:5′-TGTTTCAAATCCAGTGGATATCTTGAC-3′ (SEQ ID NO: 5651)5′-UUCAAAUCCAGUGGAUAUCUUGAcc-3′ (SEQ ID NO: 1624)3′-CAAAGUUUAGGUCACCUAUAGAACUGG-5′ (SEQ ID NO: 3638) LDHA-704 Target:5′-GTTTCAAATCCAGTGGATATCTTGACC-3′ (SEQ ID NO: 5652)5′-UCAAAUCCAGUGGAUAUCUUGACct-3′ (SEQ ID NO: 1625)3′-AAAGUUUAGGUCACCUAUAGAACUGGA-5′ (SEQ ID NO: 3639) LDHA-705 Target:5′-TTTCAAATCCAGTGGATATCTTGACCT-3′ (SEQ ID NO: 5653)5′-CAAAUCCAGUGGAUAUCUUGACCta-3′ (SEQ ID NO: 1626)3′-AAGUUUAGGUCACCUAUAGAACUGGAU-5′ (SEQ ID NO: 3640) LDHA-706 Target:5′-TTCAAATCCAGTGGATATCTTGACCTA-3′ (SEQ ID NO: 5654)5′-AAAUCCAGUGGAUAUCUUGACCUac-3′ (SEQ ID NO: 1627)3′-AGUUUAGGUCACCUAUAGAACUGGAUG-5′ (SEQ ID NO: 3641) LDHA-707 Target:5′-TCAAATCCAGTGGATATCTTGACCTAC-3′ (SEQ ID NO: 5655)5′-AAUCCAGUGGAUAUCUUGACCUAcg-3′ (SEQ ID NO: 1628)3′-GUUUAGGUCACCUAUAGAACUGGAUGC-5′ (SEQ ID NO: 3642) LDHA-708 Target:5′-CAAATCCAGTGGATATCTTGACCTACG-3′ (SEQ ID NO: 5656)5′-AUCCAGUGGAUAUCUUGACCUACgt-3′ (SEQ ID NO: 1629)3′-UUUAGGUCACCUAUAGAACUGGAUGCA-5′ (SEQ ID NO: 3643) LDHA-709 Target:5′-AAATCCAGTGGATATCTTGACCTACGT-3′ (SEQ ID NO: 5657)5′-UCCAGUGGAUAUCUUGACCUACGtg-3′ (SEQ ID NO: 1630)3′-UUAGGUCACCUAUAGAACUGGAUGCAC-5′ (SEQ ID NO: 3644) LDHA-710 Target:5′-AATCCAGTGGATATCTTGACCTACGTG-3′ (SEQ ID NO: 5658)5′-CCAGUGGAUAUCUUGACCUACGUgg-3′ (SEQ ID NO: 1631)3′-UAGGUCACCUAUAGAACUGGAUGCACC-5′ (SEQ ID NO: 3645) LDHA-711 Target:5′-ATCCAGTGGATATCTTGACCTACGTGG-3′ (SEQ ID NO: 5659)5′-CAGUGGAUAUCUUGACCUACGUGgc-3′ (SEQ ID NO: 1632)3′-AGGUCACCUAUAGAACUGGAUGCACCG-5′ (SEQ ID NO: 3646) LDHA-712 Target:5′-TCCAGTGGATATCTTGACCTACGTGGC-3′ (SEQ ID NO: 5660)5′-AGUGGAUAUCUUGACCUACGUGGct-3′ (SEQ ID NO: 1633)3′-GGUCACCUAUAGAACUGGAUGCACCGA-5′ (SEQ ID NO: 3647) LDHA-713 Target:5′-CCAGTGGATATCTTGACCTACGTGGCT-3′ (SEQ ID NO: 5661)5′-UGGAUAUCUUGACCUACGUGGCUtg-3′ (SEQ ID NO: 1634)3′-UCACCUAUAGAACUGGAUGCACCGAAC-5′ (SEQ ID NO: 3648) LDHA-715 Target:5′-AGTGGATATCTTGACCTACGTGGCTTG-3′ (SEQ ID NO: 5662)5′-GGAUAUCUUGACCUACGUGGCUUgg-3′ (SEQ ID NO: 1635)3′-CACCUAUAGAACUGGAUGCACCGAACC-5′ (SEQ ID NO: 3649) LDHA-716 Target:5′-GTGGATATCTTGACCTACGTGGCTTGG-3′ (SEQ ID NO: 5663)5′-UCUUGACCUACGUGGCUUGGAAGat-3′ (SEQ ID NO: 1636)3′-AUAGAACUGGAUGCACCGAACCUUCUA-5′ (SEQ ID NO: 3650) LDHA-721 Target:5′-TATCTTGACCTACGTGGCTTGGAAGAT-3′ (SEQ ID NO: 5664)5′-GACCUACGUGGCUUGGAAGAUAAgt-3′ (SEQ ID NO: 1637)3′-AACUGGAUGCACCGAACCUUCUAUUCA-5′ (SEQ ID NO: 3651) LDHA-725 Target:5′-TTGACCTACGTGGCTTGGAAGATAAGT-3′ (SEQ ID NO: 5665)5′-ACCUACGUGGCUUGGAAGAUAAGtg-3′ (SEQ ID NO: 1638)3′-ACUGGAUGCACCGAACCUUCUAUUCAC-5′ (SEQ ID NO: 3652) LDHA-726 Target:5′-TGACCTACGTGGCTTGGAAGATAAGTG-3′ (SEQ ID NO: 5666)5′-CCUACGUGGCUUGGAAGAUAAGUgg-3′ (SEQ ID NO: 1639)3′-CUGGAUGCACCGAACCUUCUAUUCACC-5′ (SEQ ID NO: 3653) LDHA-727 Target:5′-GACCTACGTGGCTTGGAAGATAAGTGG-3′ (SEQ ID NO: 5667)5′-CUACGUGGCUUGGAAGAUAAGUGgt-3′ (SEQ ID NO: 1640)3′-UGGAUGCACCGAACCUUCUAUUCACCA-5′ (SEQ ID NO: 3654) LDHA-728 Target:5′-ACCTACGTGGCTTGGAAGATAAGTGGT-3′ (SEQ ID NO: 5668)5′-UACGUGGCUUGGAAGAUAAGUGGtt-3′ (SEQ ID NO: 1641)3′-GGAUGCACCGAACCUUCUAUUCACCAA-5′ (SEQ ID NO: 3655) LDHA-729 Target:5′-CCTACGTGGCTTGGAAGATAAGTGGTT-3′ (SEQ ID NO: 5669)5′-ACGUGGCUUGGAAGAUAAGUGGUtt-3′ (SEQ ID NO: 1642)3′-GAUGCACCGAACCUUCUAUUCACCAAA-5′ (SEQ ID NO: 3656) LDHA-730 Target:5′-CTACGTGGCTTGGAAGATAAGTGGTTT-3′ (SEQ ID NO: 5670)5′-CGUGGCUUGGAAGAUAAGUGGUUtt-3′ (SEQ ID NO: 1643)3′-AUGCACCGAACCUUCUAUUCACCAAAA-5′ (SEQ ID NO: 3657) LDHA-731 Target:5′-TACGTGGCTTGGAAGATAAGTGGTTTT-3′ (SEQ ID NO: 5671)5′-GUGGCUUGGAAGAUAAGUGGUUUtc-3′ (SEQ ID NO: 1644)3′-UGCACCGAACCUUCUAUUCACCAAAAG-5′ (SEQ ID NO: 3658) LDHA-732 Target:5′-ACGTGGCTTGGAAGATAAGTGGTTTTC-3′ (SEQ ID NO: 5672)5′-UGGCUUGGAAGAUAAGUGGUUUUcc-3′ (SEQ ID NO: 1645)3′-GCACCGAACCUUCUAUUCACCAAAAGG-5′ (SEQ ID NO: 3659) LDHA-733 Target:5′-CGTGGCTTGGAAGATAAGTGGTTTTCC-3′ (SEQ ID NO: 5673)5′-GGCUUGGAAGAUAAGUGGUUUUCcc-3′ (SEQ ID NO: 1646)3′-CACCGAACCUUCUAUUCACCAAAAGGG-5′ (SEQ ID NO: 3660) LDHA-734 Target:5′-GTGGCTTGGAAGATAAGTGGTTTTCCC-3′ (SEQ ID NO: 5674)5′-GCUUGGAAGAUAAGUGGUUUUCCca-3′ (SEQ ID NO: 1647)3′-ACCGAACCUUCUAUUCACCAAAAGGGU-5′ (SEQ ID NO: 3661) LDHA-735 Target:5′-TGGCTTGGAAGATAAGTGGTTTTCCCA-3′ (SEQ ID NO: 5675)5′-CUUGGAAGAUAAGUGGUUUUCCCaa-3′ (SEQ ID NO: 1648)3′-CCGAACCUUCUAUUCACCAAAAGGGUU-5′ (SEQ ID NO: 3662) LDHA-736 Target:5′-GGCTTGGAAGATAAGTGGTTTTCCCAA-3′ (SEQ ID NO: 5676)5′-UUGGAAGAUAAGUGGUUUUCCCAaa-3′ (SEQ ID NO: 1649)3′-CGAACCUUCUAUUCACCAAAAGGGUUU-5′ (SEQ ID NO: 3663) LDHA-737 Target:5′-GCTTGGAAGATAAGTGGTTTTCCCAAA-3′ (SEQ ID NO: 5677)5′-UGGAAGAUAAGUGGUUUUCCCAAaa-3′ (SEQ ID NO: 1650)3′-GAACCUUCUAUUCACCAAAAGGGUUUU-5′ (SEQ ID NO: 3664) LDHA-738 Target:5′-CTTGGAAGATAAGTGGTTTTCCCAAAA-3′ (SEQ ID NO: 5678)5′-AAGAUAAGUGGUUUUCCCAAAAAcc-3′ (SEQ ID NO: 1651)3′-CCUUCUAUUCACCAAAAGGGUUUUUGG-5′ (SEQ ID NO: 3665) LDHA-741 Target:5′-GGAAGATAAGTGGTTTTCCCAAAAACC-3′ (SEQ ID NO: 5679)5′-AGAUAAGUGGUUUUCCCAAAAACcg-3′ (SEQ ID NO: 1652)3′-CUUCUAUUCACCAAAAGGGUUUUUGGC-5′ (SEQ ID NO: 3666) LDHA-742 Target:5′-GAAGATAAGTGGTTTTCCCAAAAACCG-3′ (SEQ ID NO: 5680)5′-GAUAAGUGGUUUUCCCAAAAACCgt-3′ (SEQ ID NO: 1653)3′-UUCUAUUCACCAAAAGGGUUUUUGGCA-5′ (SEQ ID NO: 3667) LDHA-743 Target:5′-AAGATAAGTGGTTTTCCCAAAAACCGT-3′ (SEQ ID NO: 5681)5′-AUAAGUGGUUUUCCCAAAAACCGtg-3′ (SEQ ID NO: 1654)3′-UCUAUUCACCAAAAGGGUUUUUGGCAC-5′ (SEQ ID NO: 3668) LDHA-744 Target:5′-AGATAAGTGGTTTTCCCAAAAACCGTG-3′ (SEQ ID NO: 5682)5′-UAAGUGGUUUUCCCAAAAACCGUgt-3′ (SEQ ID NO: 1655)3′-CUAUUCACCAAAAGGGUUUUUGGCACA-5′ (SEQ ID NO: 3669) LDHA-745 Target:5′-GATAAGTGGTTTTCCCAAAAACCGTGT-3′ (SEQ ID NO: 5683)5′-AAGUGGUUUUCCCAAAAACCGUGtt-3′ (SEQ ID NO: 1656)3′-UAUUCACCAAAAGGGUUUUUGGCACAA-5′ (SEQ ID NO: 3670) LDHA-746 Target:5′-ATAAGTGGTTTTCCCAAAAACCGTGTT-3′ (SEQ ID NO: 5684)5′-AGUGGUUUUCCCAAAAACCGUGUta-3′ (SEQ ID NO: 1657)3′-AUUCACCAAAAGGGUUUUUGGCACAAU-5′ (SEQ ID NO: 3671) LDHA-747 Target:5′-TAAGTGGTTTTCCCAAAAACCGTGTTA-3′ (SEQ ID NO: 5685)5′-GUGGUUUUCCCAAAAACCGUGUUat-3′ (SEQ ID NO: 1658)3′-UUCACCAAAAGGGUUUUUGGCACAAUA-5′ (SEQ ID NO: 3672) LDHA-748 Target:5′-AAGTGGTTTTCCCAAAAACCGTGTTAT-3′ (SEQ ID NO: 5686)5′-UGGUUUUCCCAAAAACCGUGUUAtt-3′ (SEQ ID NO: 1659)3′-UCACCAAAAGGGUUUUUGGCACAAUAA-5′ (SEQ ID NO: 3673) LDHA-749 Target:5′-AGTGGTTTTCCCAAAAACCGTGTTATT-3′ (SEQ ID NO: 5687)5′-GGUUUUCCCAAAAACCGUGUUAUtg-3′ (SEQ ID NO: 1660)3′-CACCAAAAGGGUUUUUGGCACAAUAAC-5′ (SEQ ID NO: 3674) LDHA-750 Target:5′-GTGGTTTTCCCAAAAACCGTGTTATTG-3′ (SEQ ID NO: 5688)5′-GUUUUCCCAAAAACCGUGUUAUUgg-3′ (SEQ ID NO: 1661)3′-ACCAAAAGGGUUUUUGGCACAAUAACC-5′ (SEQ ID NO: 3675) LDHA-751 Target:5′-TGGTTTTCCCAAAAACCGTGTTATTGG-3′ (SEQ ID NO: 5689)5′-UUUUCCCAAAAACCGUGUUAUUGga-3′ (SEQ ID NO: 1662)3′-CCAAAAGGGUUUUUGGCACAAUAACCU-5′ (SEQ ID NO: 3676) LDHA-752 Target:5′-GGTTTTCCCAAAAACCGTGTTATTGGA-3′ (SEQ ID NO: 5690)5′-UUUCCCAAAAACCGUGUUAUUGGaa-3′ (SEQ ID NO: 1663)3′-CAAAAGGGUUUUUGGCACAAUAACCUU-5′ (SEQ ID NO: 3677) LDHA-753 Target:5′-GTTTTCCCAAAAACCGTGTTATTGGAA-3′ (SEQ ID NO: 5691)5′-UUCCCAAAAACCGUGUUAUUGGAag-3′ (SEQ ID NO: 1664)3′-AAAAGGGUUUUUGGCACAAUAACCUUC-5′ (SEQ ID NO: 3678) LDHA-754 Target:5′-TTTTCCCAAAAACCGTGTTATTGGAAG-3′ (SEQ ID NO: 5692)5′-UCCCAAAAACCGUGUUAUUGGAAgc-3′ (SEQ ID NO: 1665)3′-AAAGGGUUUUUGGCACAAUAACCUUCG-5′ (SEQ ID NO: 3679) LDHA-755 Target:5′-TTTCCCAAAAACCGTGTTATTGGAAGC-3′ (SEQ ID NO: 5693)5′-CCCAAAAACCGUGUUAUUGGAAGcg-3′ (SEQ ID NO: 1666)3′-AAGGGUUUUUGGCACAAUAACCUUCGC-5′ (SEQ ID NO: 3680) LDHA-756 Target:5′-TTCCCAAAAACCGTGTTATTGGAAGCG-3′ (SEQ ID NO: 5694)5′-CCAAAAACCGUGUUAUUGGAAGCgg-3′ (SEQ ID NO: 1667)3′-AGGGUUUUUGGCACAAUAACCUUCGCC-5′ (SEQ ID NO: 3681) LDHA-757 Target:5′-TCCCAAAAACCGTGTTATTGGAAGCGG-3′ (SEQ ID NO: 5695)5′-CAAAAACCGUGUUAUUGGAAGCGgt-3′ (SEQ ID NO: 1668)3′-GGGUUUUUGGCACAAUAACCUUCGCCA-5′ (SEQ ID NO: 3682) LDHA-758 Target:5′-CCCAAAAACCGTGTTATTGGAAGCGGT-3′ (SEQ ID NO: 5696)5′-AAAAACCGUGUUAUUGGAAGCGGtt-3′ (SEQ ID NO: 1669)3′-GGUUUUUGGCACAAUAACCUUCGCCAA-5′ (SEQ ID NO: 3683) LDHA-759 Target:5′-CCAAAAACCGTGTTATTGGAAGCGGTT-3′ (SEQ ID NO: 5697)5′-AAAACCGUGUUAUUGGAAGCGGUtg-3′ (SEQ ID NO: 1670)3′-GUUUUUGGCACAAUAACCUUCGCCAAC-5′ (SEQ ID NO: 3684) LDHA-760 Target:5′-CAAAAACCGTGTTATTGGAAGCGGTTG-3′ (SEQ ID NO: 5698)5′-AAACCGUGUUAUUGGAAGCGGUUgc-3′ (SEQ ID NO: 1671)3′-UUUUUGGCACAAUAACCUUCGCCAACG-5′ (SEQ ID NO: 3685) LDHA-761 Target:5′-AAAAACCGTGTTATTGGAAGCGGTTGC-3′ (SEQ ID NO: 5699)5′-AACCGUGUUAUUGGAAGCGGUUGca-3′ (SEQ ID NO: 1672)3′-UUUUGGCACAAUAACCUUCGCCAACGU-5′ (SEQ ID NO: 3686) LDHA-762 Target:5′-AAAACCGTGTTATTGGAAGCGGTTGCA-3′ (SEQ ID NO: 5700)5′-ACCGUGUUAUUGGAAGCGGUUGCaa-3′ (SEQ ID NO: 1673)3′-UUUGGCACAAUAACCUUCGCCAACGUU-5′ (SEQ ID NO: 3687) LDHA-763 Target:5′-AAACCGTGTTATTGGAAGCGGTTGCAA-3′ (SEQ ID NO: 5701)5′-CCGUGUUAUUGGAAGCGGUUGCAat-3′ (SEQ ID NO: 1674)3′-UUGGCACAAUAACCUUCGCCAACGUUA-5′ (SEQ ID NO: 3688) LDHA-764 Target:5′-AACCGTGTTATTGGAAGCGGTTGCAAT-3′ (SEQ ID NO: 5702)5′-CGUGUUAUUGGAAGCGGUUGCAAtc-3′ (SEQ ID NO: 1675)3′-UGGCACAAUAACCUUCGCCAACGUUAG-5′ (SEQ ID NO: 3689) LDHA-765 Target:5′-ACCGTGTTATTGGAAGCGGTTGCAATC-3′ (SEQ ID NO: 5703)5′-GUGUUAUUGGAAGCGGUUGCAAUct-3′ (SEQ ID NO: 1676)3′-GGCACAAUAACCUUCGCCAACGUUAGA-5′ (SEQ ID NO: 3690) LDHA-766 Target:5′-CCGTGTTATTGGAAGCGGTTGCAATCT-3′ (SEQ ID NO: 5704)5′-UGUUAUUGGAAGCGGUUGCAAUCtg-3′ (SEQ ID NO: 1677)3′-GCACAAUAACCUUCGCCAACGUUAGAC-5′ (SEQ ID NO: 3691) LDHA-767 Target:5′-CGTGTTATTGGAAGCGGTTGCAATCTG-3′ (SEQ ID NO: 5705)5′-GUUAUUGGAAGCGGUUGCAAUCUgg-3′ (SEQ ID NO: 1678)3′-CACAAUAACCUUCGCCAACGUUAGACC-5′ (SEQ ID NO: 3692) LDHA-768 Target:5′-GTGTTATTGGAAGCGGTTGCAATCTGG-3′ (SEQ ID NO: 5706)5′-UUAUUGGAAGCGGUUGCAAUCUGga-3′ (SEQ ID NO: 1679)3′-ACAAUAACCUUCGCCAACGUUAGACCU-5′ (SEQ ID NO: 3693) LDHA-769 Target:5′-TGTTATTGGAAGCGGTTGCAATCTGGA-3′ (SEQ ID NO: 5707)5′-UAUUGGAAGCGGUUGCAAUCUGGat-3′ (SEQ ID NO: 1680)3′-CAAUAACCUUCGCCAACGUUAGACCUA-5′ (SEQ ID NO: 3694) LDHA-770 Target:5′-GTTATTGGAAGCGGTTGCAATCTGGAT-3′ (SEQ ID NO: 5708)5′-AUUGGAAGCGGUUGCAAUCUGGAtt-3′ (SEQ ID NO: 1681)3′-AAUAACCUUCGCCAACGUUAGACCUAA-5′ (SEQ ID NO: 3695) LDHA-771 Target:5′-TTATTGGAAGCGGTTGCAATCTGGATT-3′ (SEQ ID NO: 5709)5′-UUGGAAGCGGUUGCAAUCUGGAUtc-3′ (SEQ ID NO: 1682)3′-AUAACCUUCGCCAACGUUAGACCUAAG-5′ (SEQ ID NO: 3696) LDHA-772 Target:5′-TATTGGAAGCGGTTGCAATCTGGATTC-3′ (SEQ ID NO: 5710)5′-UGGAAGCGGUUGCAAUCUGGAUUca-3′ (SEQ ID NO: 1683)3′-UAACCUUCGCCAACGUUAGACCUAAGU-5′ (SEQ ID NO: 3697) LDHA-773 Target:5′-ATTGGAAGCGGTTGCAATCTGGATTCA-3′ (SEQ ID NO: 5711)5′-GGAAGCGGUUGCAAUCUGGAUUCag-3′ (SEQ ID NO: 1684)3′-AACCUUCGCCAACGUUAGACCUAAGUC-5′ (SEQ ID NO: 3698) LDHA-774 Target:5′-TTGGAAGCGGTTGCAATCTGGATTCAG-3′ (SEQ ID NO: 5712)5′-GAAGCGGUUGCAAUCUGGAUUCAgc-3′ (SEQ ID NO: 1685)3′-ACCUUCGCCAACGUUAGACCUAAGUCG-5′ (SEQ ID NO: 3699) LDHA-775 Target:5′-TGGAAGCGGTTGCAATCTGGATTCAGC-3′ (SEQ ID NO: 5713)5′-AAGCGGUUGCAAUCUGGAUUCAGcc-3′ (SEQ ID NO: 1686)3′-CCUUCGCCAACGUUAGACCUAAGUCGG-5′ (SEQ ID NO: 3700) LDHA-776 Target:5′-GGAAGCGGTTGCAATCTGGATTCAGCC-3′ (SEQ ID NO: 5714)5′-AGCGGUUGCAAUCUGGAUUCAGCcc-3′ (SEQ ID NO: 1687)3′-CUUCGCCAACGUUAGACCUAAGUCGGG-5′ (SEQ ID NO: 3701) LDHA-777 Target:5′-GAAGCGGTTGCAATCTGGATTCAGCCC-3′ (SEQ ID NO: 5715)5′-GCGGUUGCAAUCUGGAUUCAGCCcg-3′ (SEQ ID NO: 1688)3′-UUCGCCAACGUUAGACCUAAGUCGGGC-5′ (SEQ ID NO: 3702) LDHA-778 Target:5′-AAGCGGTTGCAATCTGGATTCAGCCCG-3′ (SEQ ID NO: 5716)5′-CGGUUGCAAUCUGGAUUCAGCCCga-3′ (SEQ ID NO: 1689)3′-UCGCCAACGUUAGACCUAAGUCGGGCU-5′ (SEQ ID NO: 3703) LDHA-779 Target:5′-AGCGGTTGCAATCTGGATTCAGCCCGA-3′ (SEQ ID NO: 5717)5′-GGUUGCAAUCUGGAUUCAGCCCGat-3′ (SEQ ID NO: 1690)3′-CGCCAACGUUAGACCUAAGUCGGGCUA-5′ (SEQ ID NO: 3704) LDHA-780 Target:5′-GCGGTTGCAATCTGGATTCAGCCCGAT-3′ (SEQ ID NO: 5718)5′-GUUGCAAUCUGGAUUCAGCCCGAtt-3′ (SEQ ID NO: 1691)3′-GCCAACGUUAGACCUAAGUCGGGCUAA-5′ (SEQ ID NO: 3705) LDHA-781 Target:5′-CGGTTGCAATCTGGATTCAGCCCGATT-3′ (SEQ ID NO: 5719)5′-UUGCAAUCUGGAUUCAGCCCGAUtc-3′ (SEQ ID NO: 1692)3′-CCAACGUUAGACCUAAGUCGGGCUAAG-5′ (SEQ ID NO: 3706) LDHA-782 Target:5′-GGTTGCAATCTGGATTCAGCCCGATTC-3′ (SEQ ID NO: 5720)5′-UGCAAUCUGGAUUCAGCCCGAUUcc-3′ (SEQ ID NO: 1693)3′-CAACGUUAGACCUAAGUCGGGCUAAGG-5′ (SEQ ID NO: 3707) LDHA-783 Target:5′-GTTGCAATCTGGATTCAGCCCGATTCC-3′ (SEQ ID NO: 5721)5′-GCAAUCUGGAUUCAGCCCGAUUCcg-3′ (SEQ ID NO: 1694)3′-AACGUUAGACCUAAGUCGGGCUAAGGC-5′ (SEQ ID NO: 3708) LDHA-784 Target:5′-TTGCAATCTGGATTCAGCCCGATTCCG-3′ (SEQ ID NO: 5722)5′-CAAUCUGGAUUCAGCCCGAUUCCgt-3′ (SEQ ID NO: 1695)3′-ACGUUAGACCUAAGUCGGGCUAAGGCA-5′ (SEQ ID NO: 3709) LDHA-785 Target:5′-TGCAATCTGGATTCAGCCCGATTCCGT-3′ (SEQ ID NO: 5723)5′-AAUCUGGAUUCAGCCCGAUUCCGtt-3′ (SEQ ID NO: 1696)3′-CGUUAGACCUAAGUCGGGCUAAGGCAA-5′ (SEQ ID NO: 3710) LDHA-786 Target:5′-GCAATCTGGATTCAGCCCGATTCCGTT-3′ (SEQ ID NO: 5724)5′-AUCUGGAUUCAGCCCGAUUCCGUta-3′ (SEQ ID NO: 1697)3′-GUUAGACCUAAGUCGGGCUAAGGCAAU-5′ (SEQ ID NO: 3711) LDHA-787 Target:5′-CAATCTGGATTCAGCCCGATTCCGTTA-3′ (SEQ ID NO: 5725)5′-UCUGGAUUCAGCCCGAUUCCGUUac-3′ (SEQ ID NO: 1698)3′-UUAGACCUAAGUCGGGCUAAGGCAAUG-5′ (SEQ ID NO: 3712) LDHA-788 Target:5′-AATCTGGATTCAGCCCGATTCCGTTAC-3′ (SEQ ID NO: 5726)5′-CUGGAUUCAGCCCGAUUCCGUUAcc-3′ (SEQ ID NO: 1699)3′-UAGACCUAAGUCGGGCUAAGGCAAUGG-5′ (SEQ ID NO: 3713) LDHA-789 Target:5′-ATCTGGATTCAGCCCGATTCCGTTACC-3′ (SEQ ID NO: 5727)5′-UGGAUUCAGCCCGAUUCCGUUACct-3′ (SEQ ID NO: 1700)3′-AGACCUAAGUCGGGCUAAGGCAAUGGA-5′ (SEQ ID NO: 3714) LDHA-790 Target:5′-TCTGGATTCAGCCCGATTCCGTTACCT-3′ (SEQ ID NO: 5728)5′-GGAUUCAGCCCGAUUCCGUUACCta-3′ (SEQ ID NO: 1701)3′-GACCUAAGUCGGGCUAAGGCAAUGGAU-5′ (SEQ ID NO: 3715) LDHA-791 Target:5′-CTGGATTCAGCCCGATTCCGTTACCTA-3′ (SEQ ID NO: 5729)5′-GAUUCAGCCCGAUUCCGUUACCUaa-3′ (SEQ ID NO: 1702)3′-ACCUAAGUCGGGCUAAGGCAAUGGAUU-5′ (SEQ ID NO: 3716) LDHA-792 Target:5′-TGGATTCAGCCCGATTCCGTTACCTAA-3′ (SEQ ID NO: 5730)5′-AUUCAGCCCGAUUCCGUUACCUAat-3′ (SEQ ID NO: 1703)3′-CCUAAGUCGGGCUAAGGCAAUGGAUUA-5′ (SEQ ID NO: 3717) LDHA-793 Target:5′-GGATTCAGCCCGATTCCGTTACCTAAT-3′ (SEQ ID NO: 5731)5′-UUCAGCCCGAUUCCGUUACCUAAtg-3′ (SEQ ID NO: 1704)3′-CUAAGUCGGGCUAAGGCAAUGGAUUAC-5′ (SEQ ID NO: 3718) LDHA-794 Target:5′-GATTCAGCCCGATTCCGTTACCTAATG-3′ (SEQ ID NO: 5732)5′-UCAGCCCGAUUCCGUUACCUAAUgg-3′ (SEQ ID NO: 1705)3′-UAAGUCGGGCUAAGGCAAUGGAUUACC-5′ (SEQ ID NO: 3719) LDHA-795 Target:5′-ATTCAGCCCGATTCCGTTACCTAATGG-3′ (SEQ ID NO: 5733)5′-CAGCCCGAUUCCGUUACCUAAUGgg-3′ (SEQ ID NO: 1706)3′-AAGUCGGGCUAAGGCAAUGGAUUACCC-5′ (SEQ ID NO: 3720) LDHA-796 Target:5′-TTCAGCCCGATTCCGTTACCTAATGGG-3′ (SEQ ID NO: 5734)5′-AGCCCGAUUCCGUUACCUAAUGGgg-3′ (SEQ ID NO: 1707)3′-AGUCGGGCUAAGGCAAUGGAUUACCCC-5′ (SEQ ID NO: 3721) LDHA-797 Target:5′-TCAGCCCGATTCCGTTACCTAATGGGG-3′ (SEQ ID NO: 5735)5′-GCCCGAUUCCGUUACCUAAUGGGgg-3′ (SEQ ID NO: 1708)3′-GUCGGGCUAAGGCAAUGGAUUACCCCC-5′ (SEQ ID NO: 3722) LDHA-798 Target:5′-CAGCCCGATTCCGTTACCTAATGGGGG-3′ (SEQ ID NO: 5736)5′-CCCGAUUCCGUUACCUAAUGGGGga-3′ (SEQ ID NO: 1709)3′-UCGGGCUAAGGCAAUGGAUUACCCCCU-5′ (SEQ ID NO: 3723) LDHA-799 Target:5′-AGCCCGATTCCGTTACCTAATGGGGGA-3′ (SEQ ID NO: 5737)5′-CCGAUUCCGUUACCUAAUGGGGGaa-3′ (SEQ ID NO: 1710)3′-CGGGCUAAGGCAAUGGAUUACCCCCUU-5′ (SEQ ID NO: 3724) LDHA-800 Target:5′-GCCCGATTCCGTTACCTAATGGGGGAA-3′ (SEQ ID NO: 5738)5′-CGAUUCCGUUACCUAAUGGGGGAaa-3′ (SEQ ID NO: 1711)3′-GGGCUAAGGCAAUGGAUUACCCCCUUU-5′ (SEQ ID NO: 3725) LDHA-801 Target:5′-CCCGATTCCGTTACCTAATGGGGGAAA-3′ (SEQ ID NO: 5739)5′-GAUUCCGUUACCUAAUGGGGGAAag-3′ (SEQ ID NO: 1712)3′-GGCUAAGGCAAUGGAUUACCCCCUUUC-5′ (SEQ ID NO: 3726) LDHA-802 Target:5′-CCGATTCCGTTACCTAATGGGGGAAAG-3′ (SEQ ID NO: 5740)5′-AUUCCGUUACCUAAUGGGGGAAAgg-3′ (SEQ ID NO: 1713)3′-GCUAAGGCAAUGGAUUACCCCCUUUCC-5′ (SEQ ID NO: 3727) LDHA-803 Target:5′-CGATTCCGTTACCTAATGGGGGAAAGG-3′ (SEQ ID NO: 5741)5′-UUCCGUUACCUAAUGGGGGAAAGgc-3′ (SEQ ID NO: 1714)3′-CUAAGGCAAUGGAUUACCCCCUUUCCG-5′ (SEQ ID NO: 3728) LDHA-804 Target:5′-GATTCCGTTACCTAATGGGGGAAAGGC-3′ (SEQ ID NO: 5742)5′-UCCGUUACCUAAUGGGGGAAAGGct-3′ (SEQ ID NO: 1715)3′-UAAGGCAAUGGAUUACCCCCUUUCCGA-5′ (SEQ ID NO: 3729) LDHA-805 Target:5′-ATTCCGTTACCTAATGGGGGAAAGGCT-3′ (SEQ ID NO: 5743)5′-CCGUUACCUAAUGGGGGAAAGGCtg-3′ (SEQ ID NO: 1716)3′-AAGGCAAUGGAUUACCCCCUUUCCGAC-5′ (SEQ ID NO: 3730) LDHA-806 Target:5′-TTCCGTTACCTAATGGGGGAAAGGCTG-3′ (SEQ ID NO: 5744)5′-CGUUACCUAAUGGGGGAAAGGCUgg-3′ (SEQ ID NO: 1717)3′-AGGCAAUGGAUUACCCCCUUUCCGACC-5′ (SEQ ID NO: 3731) LDHA-807 Target:5′-TCCGTTACCTAATGGGGGAAAGGCTGG-3′ (SEQ ID NO: 5745)5′-GUUACCUAAUGGGGGAAAGGCUGgg-3′ (SEQ ID NO: 1718)3′-GGCAAUGGAUUACCCCCUUUCCGACCC-5′ (SEQ ID NO: 3732) LDHA-808 Target:5′-CCGTTACCTAATGGGGGAAAGGCTGGG-3′ (SEQ ID NO: 5746)5′-UUACCUAAUGGGGGAAAGGCUGGga-3′ (SEQ ID NO: 1719)3′-GCAAUGGAUUACCCCCUUUCCGACCCU-5′ (SEQ ID NO: 3733) LDHA-809 Target:5′-CGTTACCTAATGGGGGAAAGGCTGGGA-3′ (SEQ ID NO: 5747)5′-UACCUAAUGGGGGAAAGGCUGGGag-3′ (SEQ ID NO: 1720)3′-CAAUGGAUUACCCCCUUUCCGACCCUC-5′ (SEQ ID NO: 3734) LDHA-810 Target:5′-GTTACCTAATGGGGGAAAGGCTGGGAG-3′ (SEQ ID NO: 5748)5′-ACCUAAUGGGGGAAAGGCUGGGAgt-3′ (SEQ ID NO: 1721)3′-AAUGGAUUACCCCCUUUCCGACCCUCA-5′ (SEQ ID NO: 3735) LDHA-811 Target:5′-TTACCTAATGGGGGAAAGGCTGGGAGT-3′ (SEQ ID NO: 5749)5′-CCUAAUGGGGGAAAGGCUGGGAGtt-3′ (SEQ ID NO: 1722)3′-AUGGAUUACCCCCUUUCCGACCCUCAA-5′ (SEQ ID NO: 3736) LDHA-812 Target:5′-TACCTAATGGGGGAAAGGCTGGGAGTT-3′ (SEQ ID NO: 5750)5′-CUAAUGGGGGAAAGGCUGGGAGUtc-3′ (SEQ ID NO: 1723)3′-UGGAUUACCCCCUUUCCGACCCUCAAG-5′ (SEQ ID NO: 3737) LDHA-813 Target:5′-ACCTAATGGGGGAAAGGCTGGGAGTTC-3′ (SEQ ID NO: 5751)5′-UAAUGGGGGAAAGGCUGGGAGUUca-3′ (SEQ ID NO: 1724)3′-GGAUUACCCCCUUUCCGACCCUCAAGU-5′ (SEQ ID NO: 3738) LDHA-814 Target:5′-CCTAATGGGGGAAAGGCTGGGAGTTCA-3′ (SEQ ID NO: 5752)5′-AAUGGGGGAAAGGCUGGGAGUUCac-3′ (SEQ ID NO: 1725)3′-GAUUACCCCCUUUCCGACCCUCAAGUG-5′ (SEQ ID NO: 3739) LDHA-815 Target:5′-CTAATGGGGGAAAGGCTGGGAGTTCAC-3′ (SEQ ID NO: 5753)5′-AUGGGGGAAAGGCUGGGAGUUCAcc-3′ (SEQ ID NO: 1726)3′-AUUACCCCCUUUCCGACCCUCAAGUGG-5′ (SEQ ID NO: 3740) LDHA-816 Target:5′-TAATGGGGGAAAGGCTGGGAGTTCACC-3′ (SEQ ID NO: 5754)5′-UGGGGGAAAGGCUGGGAGUUCACcc-3′ (SEQ ID NO: 1727)3′-UUACCCCCUUUCCGACCCUCAAGUGGG-5′ (SEQ ID NO: 3741) LDHA-817 Target:5′-AATGGGGGAAAGGCTGGGAGTTCACCC-3′ (SEQ ID NO: 5755)5′-GGGGGAAAGGCUGGGAGUUCACCca-3′ (SEQ ID NO: 1728)3′-UACCCCCUUUCCGACCCUCAAGUGGGU-5′ (SEQ ID NO: 3742) LDHA-818 Target:5′-ATGGGGGAAAGGCTGGGAGTTCACCCA-3′ (SEQ ID NO: 5756)5′-GGGGAAAGGCUGGGAGUUCACCCat-3′ (SEQ ID NO: 1729)3′-ACCCCCUUUCCGACCCUCAAGUGGGUA-5′ (SEQ ID NO: 3743) LDHA-819 Target:5′-TGGGGGAAAGGCTGGGAGTTCACCCAT-3′ (SEQ ID NO: 5757)5′-GGGAAAGGCUGGGAGUUCACCCAtt-3′ (SEQ ID NO: 1730)3′-CCCCCUUUCCGACCCUCAAGUGGGUAA-5′ (SEQ ID NO: 3744) LDHA-820 Target:5′-GGGGGAAAGGCTGGGAGTTCACCCATT-3′ (SEQ ID NO: 5758)5′-GGAAAGGCUGGGAGUUCACCCAUta-3′ (SEQ ID NO: 1731)3′-CCCCUUUCCGACCCUCAAGUGGGUAAU-5′ (SEQ ID NO: 3745) LDHA-821 Target:5′-GGGGAAAGGCTGGGAGTTCACCCATTA-3′ (SEQ ID NO: 5759)5′-GAAAGGCUGGGAGUUCACCCAUUaa-3′ (SEQ ID NO: 1732)3′-CCCUUUCCGACCCUCAAGUGGGUAAUU-5′ (SEQ ID NO: 3746) LDHA-822 Target:5′-GGGAAAGGCTGGGAGTTCACCCATTAA-3′ (SEQ ID NO: 5760)5′-AAAGGCUGGGAGUUCACCCAUUAag-3′ (SEQ ID NO: 1733)3′-CCUUUCCGACCCUCAAGUGGGUAAUUC-5′ (SEQ ID NO: 3747) LDHA-823 Target:5′-GGAAAGGCTGGGAGTTCACCCATTAAG-3′ (SEQ ID NO: 5761)5′-AAGGCUGGGAGUUCACCCAUUAAgc-3′ (SEQ ID NO: 1734)3′-CUUUCCGACCCUCAAGUGGGUAAUUCG-5′ (SEQ ID NO: 3748) LDHA-824 Target:5′-GAAAGGCTGGGAGTTCACCCATTAAGC-3′ (SEQ ID NO: 5762)5′-AGGCUGGGAGUUCACCCAUUAAGct-3′ (SEQ ID NO: 1735)3′-UUUCCGACCCUCAAGUGGGUAAUUCGA-5′ (SEQ ID NO: 3749) LDHA-825 Target:5′-AAAGGCTGGGAGTTCACCCATTAAGCT-3′ (SEQ ID NO: 5763)5′-GGCUGGGAGUUCACCCAUUAAGCtg-3′ (SEQ ID NO: 1736)3′-UUCCGACCCUCAAGUGGGUAAUUCGAC-5′ (SEQ ID NO: 3750) LDHA-826 Target:5′-AAGGCTGGGAGTTCACCCATTAAGCTG-3′ (SEQ ID NO: 5764)5′-GCUGGGAGUUCACCCAUUAAGCUgt-3′ (SEQ ID NO: 1737)3′-UCCGACCCUCAAGUGGGUAAUUCGACA-5′ (SEQ ID NO: 3751) LDHA-827 Target:5′-AGGCTGGGAGTTCACCCATTAAGCTGT-3′ (SEQ ID NO: 5765)5′-CUGGGAGUUCACCCAUUAAGCUGtc-3′ (SEQ ID NO: 1738)3′-CCGACCCUCAAGUGGGUAAUUCGACAG-5′ (SEQ ID NO: 3752) LDHA-828 Target:5′-GGCTGGGAGTTCACCCATTAAGCTGTC-3′ (SEQ ID NO: 5766)5′-UGGGAGUUCACCCAUUAAGCUGUca-3′ (SEQ ID NO: 1739)3′-CGACCCUCAAGUGGGUAAUUCGACAGU-5′ (SEQ ID NO: 3753) LDHA-829 Target:5′-GCTGGGAGTTCACCCATTAAGCTGTCA-3′ (SEQ ID NO: 5767)5′-GGGAGUUCACCCAUUAAGCUGUCat-3′ (SEQ ID NO: 1740)3′-GACCCUCAAGUGGGUAAUUCGACAGUA-5′ (SEQ ID NO: 3754) LDHA-830 Target:5′-CTGGGAGTTCACCCATTAAGCTGTCAT-3′ (SEQ ID NO: 5768)5′-GGAGUUCACCCAUUAAGCUGUCAtg-3′ (SEQ ID NO: 1741)3′-ACCCUCAAGUGGGUAAUUCGACAGUAC-5′ (SEQ ID NO: 3755) LDHA-831 Target:5′-TGGGAGTTCACCCATTAAGCTGTCATG-3′ (SEQ ID NO: 5769)5′-GAGUUCACCCAUUAAGCUGUCAUgg-3′ (SEQ ID NO: 1742)3′-CCCUCAAGUGGGUAAUUCGACAGUACC-5′ (SEQ ID NO: 3756) LDHA-832 Target:5′-GGGAGTTCACCCATTAAGCTGTCATGG-3′ (SEQ ID NO: 5770)5′-AGUUCACCCAUUAAGCUGUCAUGgg-3′ (SEQ ID NO: 1743)3′-CCUCAAGUGGGUAAUUCGACAGUACCC-5′ (SEQ ID NO: 3757) LDHA-833 Target:5′-GGAGTTCACCCATTAAGCTGTCATGGG-3′ (SEQ ID NO: 5771)5′-GUUCACCCAUUAAGCUGUCAUGGgt-3′ (SEQ ID NO: 1744)3′-CUCAAGUGGGUAAUUCGACAGUACCCA-5′ (SEQ ID NO: 3758) LDHA-834 Target:5′-GAGTTCACCCATTAAGCTGTCATGGGT-3′ (SEQ ID NO: 5772)5′-UUCACCCAUUAAGCUGUCAUGGGtg-3′ (SEQ ID NO: 1745)3′-UCAAGUGGGUAAUUCGACAGUACCCAC-5′ (SEQ ID NO: 3759) LDHA-835 Target:5′-AGTTCACCCATTAAGCTGTCATGGGTG-3′ (SEQ ID NO: 5773)5′-UCACCCAUUAAGCUGUCAUGGGUgg-3′ (SEQ ID NO: 1746)3′-CAAGUGGGUAAUUCGACAGUACCCACC-5′ (SEQ ID NO: 3760) LDHA-836 Target:5′-GTTCACCCATTAAGCTGTCATGGGTGG-3′ (SEQ ID NO: 5774)5′-CACCCAUUAAGCUGUCAUGGGUGgg-3′ (SEQ ID NO: 1747)3′-AAGUGGGUAAUUCGACAGUACCCACCC-5′ (SEQ ID NO: 3761) LDHA-837 Target:5′-TTCACCCATTAAGCTGTCATGGGTGGG-3′ (SEQ ID NO: 5775)5′-ACCCAUUAAGCUGUCAUGGGUGGgt-3′ (SEQ ID NO: 1748)3′-AGUGGGUAAUUCGACAGUACCCACCCA-5′ (SEQ ID NO: 3762) LDHA-838 Target:5′-TCACCCATTAAGCTGTCATGGGTGGGT-3′ (SEQ ID NO: 5776)5′-CCCAUUAAGCUGUCAUGGGUGGGtc-3′ (SEQ ID NO: 1749)3′-GUGGGUAAUUCGACAGUACCCACCCAG-5′ (SEQ ID NO: 3763) LDHA-839 Target:5′-CACCCATTAAGCTGTCATGGGTGGGTC-3′ (SEQ ID NO: 5777)5′-CCAUUAAGCUGUCAUGGGUGGGUcc-3′ (SEQ ID NO: 1750)3′-UGGGUAAUUCGACAGUACCCACCCAGG-5′ (SEQ ID NO: 3764) LDHA-840 Target:5′-ACCCATTAAGCTGTCATGGGTGGGTCC-3′ (SEQ ID NO: 5778)5′-CAUUAAGCUGUCAUGGGUGGGUCct-3′ (SEQ ID NO: 1751)3′-GGGUAAUUCGACAGUACCCACCCAGGA-5′ (SEQ ID NO: 3765) LDHA-841 Target:5′-CCCATTAAGCTGTCATGGGTGGGTCCT-3′ (SEQ ID NO: 5779)5′-AUUAAGCUGUCAUGGGUGGGUCCtt-3′ (SEQ ID NO: 1752)3′-GGUAAUUCGACAGUACCCACCCAGGAA-5′ (SEQ ID NO: 3766) LDHA-842 Target:5′-CCATTAAGCTGTCATGGGTGGGTCCTT-3′ (SEQ ID NO: 5780)5′-UUAAGCUGUCAUGGGUGGGUCCUtg-3′ (SEQ ID NO: 1753)3′-GUAAUUCGACAGUACCCACCCAGGAAC-5′ (SEQ ID NO: 3767) LDHA-843 Target:5′-CATTAAGCTGTCATGGGTGGGTCCTTG-3′ (SEQ ID NO: 5781)5′-UAAGCUGUCAUGGGUGGGUCCUUgg-3′ (SEQ ID NO: 1754)3′-UAAUUCGACAGUACCCACCCAGGAACC-5′ (SEQ ID NO: 3768) LDHA-844 Target:5′-ATTAAGCTGTCATGGGTGGGTCCTTGG-3′ (SEQ ID NO: 5782)5′-AAGCUGUCAUGGGUGGGUCCUUGgg-3′ (SEQ ID NO: 1755)3′-AAUUCGACAGUACCCACCCAGGAACCC-5′ (SEQ ID NO: 3769) LDHA-845 Target:5′-TTAAGCTGTCATGGGTGGGTCCTTGGG-3′ (SEQ ID NO: 5783)5′-AGCUGUCAUGGGUGGGUCCUUGGgg-3′ (SEQ ID NO: 1756)3′-AUUCGACAGUACCCACCCAGGAACCCC-5′ (SEQ ID NO: 3770) LDHA-846 Target:5′-TAAGCTGTCATGGGTGGGTCCTTGGGG-3′ (SEQ ID NO: 5784)5′-GCUGUCAUGGGUGGGUCCUUGGGga-3′ (SEQ ID NO: 1757)3′-UUCGACAGUACCCACCCAGGAACCCCU-5′ (SEQ ID NO: 3771) LDHA-847 Target:5′-AAGCTGTCATGGGTGGGTCCTTGGGGA-3′ (SEQ ID NO: 5785)5′-CUGUCAUGGGUGGGUCCUUGGGGaa-3′ (SEQ ID NO: 1758)3′-UCGACAGUACCCACCCAGGAACCCCUU-5′ (SEQ ID NO: 3772) LDHA-848 Target:5′-AGCTGTCATGGGTGGGTCCTTGGGGAA-3′ (SEQ ID NO: 5786)5′-UGUCAUGGGUGGGUCCUUGGGGAac-3′ (SEQ ID NO: 1759)3′-CGACAGUACCCACCCAGGAACCCCUUG-5′ (SEQ ID NO: 3773) LDHA-849 Target:5′-GCTGTCATGGGTGGGTCCTTGGGGAAC-3′ (SEQ ID NO: 5787)5′-GUCAUGGGUGGGUCCUUGGGGAAca-3′ (SEQ ID NO: 1760)3′-GACAGUACCCACCCAGGAACCCCUUGU-5′ (SEQ ID NO: 3774) LDHA-850 Target:5′-CTGTCATGGGTGGGTCCTTGGGGAACA-3′ (SEQ ID NO: 5788)5′-UCAUGGGUGGGUCCUUGGGGAACat-3′ (SEQ ID NO: 1761)3′-ACAGUACCCACCCAGGAACCCCUUGUA-5′ (SEQ ID NO: 3775) LDHA-851 Target:5′-TGTCATGGGTGGGTCCTTGGGGAACAT-3′ (SEQ ID NO: 5789)5′-CAUGGGUGGGUCCUUGGGGAACAtg-3′ (SEQ ID NO: 1762)3′-CAGUACCCACCCAGGAACCCCUUGUAC-5′ (SEQ ID NO: 3776) LDHA-852 Target:5′-GTCATGGGTGGGTCCTTGGGGAACATG-3′ (SEQ ID NO: 5790)5′-AUGGGUGGGUCCUUGGGGAACAUgg-3′ (SEQ ID NO: 1763)3′-AGUACCCACCCAGGAACCCCUUGUACC-5′ (SEQ ID NO: 3777) LDHA-853 Target:5′-TCATGGGTGGGTCCTTGGGGAACATGG-3′ (SEQ ID NO: 5791)5′-UGGGUGGGUCCUUGGGGAACAUGga-3′ (SEQ ID NO: 1764)3′-GUACCCACCCAGGAACCCCUUGUACCU-5′ (SEQ ID NO: 3778) LDHA-854 Target:5′-CATGGGTGGGTCCTTGGGGAACATGGA-3′ (SEQ ID NO: 5792)5′-GGGUGGGUCCUUGGGGAACAUGGag-3′ (SEQ ID NO: 1765)3′-UACCCACCCAGGAACCCCUUGUACCUC-5′ (SEQ ID NO: 3779) LDHA-855 Target:5′-ATGGGTGGGTCCTTGGGGAACATGGAG-3′ (SEQ ID NO: 5793)5′-GGUGGGUCCUUGGGGAACAUGGAga-3′ (SEQ ID NO: 1766)3′-ACCCACCCAGGAACCCCUUGUACCUCU-5′ (SEQ ID NO: 3780) LDHA-856 Target:5′-TGGGTGGGTCCTTGGGGAACATGGAGA-3′ (SEQ ID NO: 5794)5′-GUGGGUCCUUGGGGAACAUGGAGat-3′ (SEQ ID NO: 1767)3′-CCCACCCAGGAACCCCUUGUACCUCUA-5′ (SEQ ID NO: 3781) LDHA-857 Target:5′-GGGTGGGTCCTTGGGGAACATGGAGAT-3′ (SEQ ID NO: 5795)5′-UGGGUCCUUGGGGAACAUGGAGAtt-3′ (SEQ ID NO: 1768)3′-CCACCCAGGAACCCCUUGUACCUCUAA-5′ (SEQ ID NO: 3782) LDHA-858 Target:5′-GGTGGGTCCTTGGGGAACATGGAGATT-3′ (SEQ ID NO: 5796)5′-GGGUCCUUGGGGAACAUGGAGAUtc-3′ (SEQ ID NO: 1769)3′-CACCCAGGAACCCCUUGUACCUCUAAG-5′ (SEQ ID NO: 3783) LDHA-859 Target:5′-GTGGGTCCTTGGGGAACATGGAGATTC-3′ (SEQ ID NO: 5797)5′-GGUCCUUGGGGAACAUGGAGAUUcc-3′ (SEQ ID NO: 1770)3′-ACCCAGGAACCCCUUGUACCUCUAAGG-5′ (SEQ ID NO: 3784) LDHA-860 Target:5′-TGGGTCCTTGGGGAACATGGAGATTCC-3′ (SEQ ID NO: 5798)5′-GUCCUUGGGGAACAUGGAGAUUCca-3′ (SEQ ID NO: 1771)3′-CCCAGGAACCCCUUGUACCUCUAAGGU-5′ (SEQ ID NO: 3785) LDHA-861 Target:5′-GGGTCCTTGGGGAACATGGAGATTCCA-3′ (SEQ ID NO: 5799)5′-UCCUUGGGGAACAUGGAGAUUCCag-3′ (SEQ ID NO: 1772)3′-CCAGGAACCCCUUGUACCUCUAAGGUC-5′ (SEQ ID NO: 3786) LDHA-862 Target:5′-GGTCCTTGGGGAACATGGAGATTCCAG-3′ (SEQ ID NO: 5800)5′-CCUUGGGGAACAUGGAGAUUCCAgt-3′ (SEQ ID NO: 1773)3′-CAGGAACCCCUUGUACCUCUAAGGUCA-5′ (SEQ ID NO: 3787) LDHA-863 Target:5′-GTCCTTGGGGAACATGGAGATTCCAGT-3′ (SEQ ID NO: 5801)5′-CUUGGGGAACAUGGAGAUUCCAGtg-3′ (SEQ ID NO: 1774)3′-AGGAACCCCUUGUACCUCUAAGGUCAC-5′ (SEQ ID NO: 3788) LDHA-864 Target:5′-TCCTTGGGGAACATGGAGATTCCAGTG-3′ (SEQ ID NO: 5802)5′-UUGGGGAACAUGGAGAUUCCAGUgt-3′ (SEQ ID NO: 1775)3′-GGAACCCCUUGUACCUCUAAGGUCACA-5′ (SEQ ID NO: 3789) LDHA-865 Target:5′-CCTTGGGGAACATGGAGATTCCAGTGT-3′ (SEQ ID NO: 5803)5′-UGGGGAACAUGGAGAUUCCAGUGtg-3′ (SEQ ID NO: 1776)3′-GAACCCCUUGUACCUCUAAGGUCACAC-5′ (SEQ ID NO: 3790) LDHA-866 Target:5′-CTTGGGGAACATGGAGATTCCAGTGTG-3′ (SEQ ID NO: 5804)5′-GGGGAACAUGGAGAUUCCAGUGUgc-3′ (SEQ ID NO: 1777)3′-AACCCCUUGUACCUCUAAGGUCACACG-5′ (SEQ ID NO: 3791) LDHA-867 Target:5′-TTGGGGAACATGGAGATTCCAGTGTGC-3′ (SEQ ID NO: 5805)5′-GGGAACAUGGAGAUUCCAGUGUGcc-3′ (SEQ ID NO: 1778)3′-ACCCCUUGUACCUCUAAGGUCACACGG-5′ (SEQ ID NO: 3792) LDHA-868 Target:5′-TGGGGAACATGGAGATTCCAGTGTGCC-3′ (SEQ ID NO: 5806)5′-GGAACAUGGAGAUUCCAGUGUGCct-3′ (SEQ ID NO: 1779)3′-CCCCUUGUACCUCUAAGGUCACACGGA-5′ (SEQ ID NO: 3793) LDHA-869 Target:5′-GGGGAACATGGAGATTCCAGTGTGCCT-3′ (SEQ ID NO: 5807)5′-GAACAUGGAGAUUCCAGUGUGCCtg-3′ (SEQ ID NO: 1780)3′-CCCUUGUACCUCUAAGGUCACACGGAC-5′ (SEQ ID NO: 3794) LDHA-870 Target:5′-GGGAACATGGAGATTCCAGTGTGCCTG-3′ (SEQ ID NO: 5808)5′-AACAUGGAGAUUCCAGUGUGCCUgt-3′ (SEQ ID NO: 1781)3′-CCUUGUACCUCUAAGGUCACACGGACA-5′ (SEQ ID NO: 3795) LDHA-871 Target:5′-GGAACATGGAGATTCCAGTGTGCCTGT-3′ (SEQ ID NO: 5809)5′-ACAUGGAGAUUCCAGUGUGCCUGta-3′ (SEQ ID NO: 1782)3′-CUUGUACCUCUAAGGUCACACGGACAU-5′ (SEQ ID NO: 3796) LDHA-872 Target:5′-GAACATGGAGATTCCAGTGTGCCTGTA-3′ (SEQ ID NO: 5810)5′-CAUGGAGAUUCCAGUGUGCCUGUat-3′ (SEQ ID NO: 1783)3′-UUGUACCUCUAAGGUCACACGGACAUA-5′ (SEQ ID NO: 3797) LDHA-873 Target:5′-AACATGGAGATTCCAGTGTGCCTGTAT-3′ (SEQ ID NO: 5811)5′-AUGGAGAUUCCAGUGUGCCUGUAtg-3′ (SEQ ID NO: 1784)3′-UGUACCUCUAAGGUCACACGGACAUAC-5′ (SEQ ID NO: 3798) LDHA-874 Target:5′-ACATGGAGATTCCAGTGTGCCTGTATG-3′ (SEQ ID NO: 5812)5′-UGGAGAUUCCAGUGUGCCUGUAUgg-3′ (SEQ ID NO: 1785)3′-GUACCUCUAAGGUCACACGGACAUACC-5′ (SEQ ID NO: 3799) LDHA-875 Target:5′-CATGGAGATTCCAGTGTGCCTGTATGG-3′ (SEQ ID NO: 5813)5′-GGAGAUUCCAGUGUGCCUGUAUGga-3′ (SEQ ID NO: 1786)3′-UACCUCUAAGGUCACACGGACAUACCU-5′ (SEQ ID NO: 3800) LDHA-876 Target:5′-ATGGAGATTCCAGTGTGCCTGTATGGA-3′ (SEQ ID NO: 5814)5′-GAGAUUCCAGUGUGCCUGUAUGGag-3′ (SEQ ID NO: 1787)3′-ACCUCUAAGGUCACACGGACAUACCUC-5′ (SEQ ID NO: 3801) LDHA-877 Target:5′-TGGAGATTCCAGTGTGCCTGTATGGAG-3′ (SEQ ID NO: 5815)5′-AGAUUCCAGUGUGCCUGUAUGGAgt-3′ (SEQ ID NO: 1788)3′-CCUCUAAGGUCACACGGACAUACCUCA-5′ (SEQ ID NO: 3802) LDHA-878 Target:5′-GGAGATTCCAGTGTGCCTGTATGGAGT-3′ (SEQ ID NO: 5816)5′-GAUUCCAGUGUGCCUGUAUGGAGtg-3′ (SEQ ID NO: 1789)3′-CUCUAAGGUCACACGGACAUACCUCAC-5′ (SEQ ID NO: 3803) LDHA-879 Target:5′-GAGATTCCAGTGTGCCTGTATGGAGTG-3′ (SEQ ID NO: 5817)5′-AUUCCAGUGUGCCUGUAUGGAGUgg-3′ (SEQ ID NO: 1790)3′-UCUAAGGUCACACGGACAUACCUCACC-5′ (SEQ ID NO: 3804) LDHA-880 Target:5′-AGATTCCAGTGTGCCTGTATGGAGTGG-3′ (SEQ ID NO: 5818)5′-UUCCAGUGUGCCUGUAUGGAGUGga-3′ (SEQ ID NO: 1791)3′-CUAAGGUCACACGGACAUACCUCACCU-5′ (SEQ ID NO: 3805) LDHA-881 Target:5′-GATTCCAGTGTGCCTGTATGGAGTGGA-3′ (SEQ ID NO: 5819)5′-UCCAGUGUGCCUGUAUGGAGUGGaa-3′ (SEQ ID NO: 1792)3′-UAAGGUCACACGGACAUACCUCACCUU-5′ (SEQ ID NO: 3806) LDHA-882 Target:5′-ATTCCAGTGTGCCTGTATGGAGTGGAA-3′ (SEQ ID NO: 5820)5′-CCAGUGUGCCUGUAUGGAGUGGAat-3′ (SEQ ID NO: 1793)3′-AAGGUCACACGGACAUACCUCACCUUA-5′ (SEQ ID NO: 3807) LDHA-883 Target:5′-TTCCAGTGTGCCTGTATGGAGTGGAAT-3′ (SEQ ID NO: 5821)5′-CAGUGUGCCUGUAUGGAGUGGAAtg-3′ (SEQ ID NO: 1794)3′-AGGUCACACGGACAUACCUCACCUUAC-5′ (SEQ ID NO: 3808) LDHA-884 Target:5′-TCCAGTGTGCCTGTATGGAGTGGAATG-3′ (SEQ ID NO: 5822)5′-AGUGUGCCUGUAUGGAGUGGAAUga-3′ (SEQ ID NO: 1795)3′-GGUCACACGGACAUACCUCACCUUACU-5′ (SEQ ID NO: 3809) LDHA-885 Target:5′-CCAGTGTGCCTGTATGGAGTGGAATGA-3′ (SEQ ID NO: 5823)5′-GUGUGCCUGUAUGGAGUGGAAUGaa-3′ (SEQ ID NO: 1796)3′-GUCACACGGACAUACCUCACCUUACUU-5′ (SEQ ID NO: 3810) LDHA-886 Target:5′-CAGTGTGCCTGTATGGAGTGGAATGAA-3′ (SEQ ID NO: 5824)5′-UGUGCCUGUAUGGAGUGGAAUGAat-3′ (SEQ ID NO: 1797)3′-UCACACGGACAUACCUCACCUUACUUA-5′ (SEQ ID NO: 3811) LDHA-887 Target:5′-AGTGTGCCTGTATGGAGTGGAATGAAT-3′ (SEQ ID NO: 5825)5′-GUGCCUGUAUGGAGUGGAAUGAAtg-3′ (SEQ ID NO: 1798)3′-CACACGGACAUACCUCACCUUACUUAC-5′ (SEQ ID NO: 3812) LDHA-888 Target:5′-GTGTGCCTGTATGGAGTGGAATGAATG-3′ (SEQ ID NO: 5826)5′-UGCCUGUAUGGAGUGGAAUGAAUgt-3′ (SEQ ID NO: 1799)3′-ACACGGACAUACCUCACCUUACUUACA-5′ (SEQ ID NO: 3813) LDHA-889 Target:5′-TGTGCCTGTATGGAGTGGAATGAATGT-3′ (SEQ ID NO: 5827)5′-GCCUGUAUGGAGUGGAAUGAAUGtt-3′ (SEQ ID NO: 1800)3′-CACGGACAUACCUCACCUUACUUACAA-5′ (SEQ ID NO: 3814) LDHA-890 Target:5′-GTGCCTGTATGGAGTGGAATGAATGTT-3′ (SEQ ID NO: 5828)5′-UGUAUGGAGUGGAAUGAAUGUUGct-3′ (SEQ ID NO: 1801)3′-GGACAUACCUCACCUUACUUACAACGA-5′ (SEQ ID NO: 3815) LDHA-893 Target:5′-CCTGTATGGAGTGGAATGAATGTTGCT-3′ (SEQ ID NO: 5829)5′-GUAUGGAGUGGAAUGAAUGUUGCtg-3′ (SEQ ID NO: 1802)3′-GACAUACCUCACCUUACUUACAACGAC-5′ (SEQ ID NO: 3816) LDHA-894 Target:5′-CTGTATGGAGTGGAATGAATGTTGCTG-3′ (SEQ ID NO: 5830)5′-UAUGGAGUGGAAUGAAUGUUGCUgg-3′ (SEQ ID NO: 1803)3′-ACAUACCUCACCUUACUUACAACGACC-5′ (SEQ ID NO: 3817) LDHA-895 Target:5′-TGTATGGAGTGGAATGAATGTTGCTGG-3′ (SEQ ID NO: 5831)5′-AUGGAGUGGAAUGAAUGUUGCUGgt-3′ (SEQ ID NO: 1804)3′-CAUACCUCACCUUACUUACAACGACCA-5′ (SEQ ID NO: 3818) LDHA-896 Target:5′-GTATGGAGTGGAATGAATGTTGCTGGT-3′ (SEQ ID NO: 5832)5′-UGGAGUGGAAUGAAUGUUGCUGGtg-3′ (SEQ ID NO: 1805)3′-AUACCUCACCUUACUUACAACGACCAC-5′ (SEQ ID NO: 3819) LDHA-897 Target:5′-TATGGAGTGGAATGAATGTTGCTGGTG-3′ (SEQ ID NO: 5833)5′-GGAGUGGAAUGAAUGUUGCUGGUgt-3′ (SEQ ID NO: 1806)3′-UACCUCACCUUACUUACAACGACCACA-5′ (SEQ ID NO: 3820) LDHA-898 Target:5′-ATGGAGTGGAATGAATGTTGCTGGTGT-3′ (SEQ ID NO: 5834)5′-GAGUGGAAUGAAUGUUGCUGGUGtc-3′ (SEQ ID NO: 1807)3′-ACCUCACCUUACUUACAACGACCACAG-5′ (SEQ ID NO: 3821) LDHA-899 Target:5′-TGGAGTGGAATGAATGTTGCTGGTGTC-3′ (SEQ ID NO: 5835)5′-AGUGGAAUGAAUGUUGCUGGUGUct-3′ (SEQ ID NO: 1808)3′-CCUCACCUUACUUACAACGACCACAGA-5′ (SEQ ID NO: 3822) LDHA-900 Target:5′-GGAGTGGAATGAATGTTGCTGGTGTCT-3′ (SEQ ID NO: 5836)5′-GUGGAAUGAAUGUUGCUGGUGUCtc-3′ (SEQ ID NO: 1809)3′-CUCACCUUACUUACAACGACCACAGAG-5′ (SEQ ID NO: 3823) LDHA-901 Target:5′-GAGTGGAATGAATGTTGCTGGTGTCTC-3′ (SEQ ID NO: 5837)5′-UGGAAUGAAUGUUGCUGGUGUCUct-3′ (SEQ ID NO: 1810)3′-UCACCUUACUUACAACGACCACAGAGA-5′ (SEQ ID NO: 3824) LDHA-902 Target:5′-AGTGGAATGAATGTTGCTGGTGTCTCT-3′ (SEQ ID NO: 5838)5′-GGAAUGAAUGUUGCUGGUGUCUCtc-3′ (SEQ ID NO: 1811)3′-CACCUUACUUACAACGACCACAGAGAG-5′ (SEQ ID NO: 3825) LDHA-903 Target:5′-GTGGAATGAATGTTGCTGGTGTCTCTC-3′ (SEQ ID NO: 5839)5′-GAAUGAAUGUUGCUGGUGUCUCUct-3′ (SEQ ID NO: 1812)3′-ACCUUACUUACAACGACCACAGAGAGA-5′ (SEQ ID NO: 3826) LDHA-904 Target:5′-TGGAATGAATGTTGCTGGTGTCTCTCT-3′ (SEQ ID NO: 5840)5′-AAUGAAUGUUGCUGGUGUCUCUCtg-3′ (SEQ ID NO: 1813)3′-CCUUACUUACAACGACCACAGAGAGAC-5′ (SEQ ID NO: 3827) LDHA-905 Target:5′-GGAATGAATGTTGCTGGTGTCTCTCTG-3′ (SEQ ID NO: 5841)5′-AUGAAUGUUGCUGGUGUCUCUCUga-3′ (SEQ ID NO: 1814)3′-CUUACUUACAACGACCACAGAGAGACU-5′ (SEQ ID NO: 3828) LDHA-906 Target:5′-GAATGAATGTTGCTGGTGTCTCTCTGA-3′ (SEQ ID NO: 5842)5′-GAAUGUUGCUGGUGUCUCUCUGAag-3′ (SEQ ID NO: 1815)3′-UACUUACAACGACCACAGAGAGACUUC-5′ (SEQ ID NO: 3829) LDHA-908 Target:5′-ATGAATGTTGCTGGTGTCTCTCTGAAG-3′ (SEQ ID NO: 5843)5′-AAUGUUGCUGGUGUCUCUCUGAAga-3′ (SEQ ID NO: 1816)3′-ACUUACAACGACCACAGAGAGACUUCU-5′ (SEQ ID NO: 3830) LDHA-909 Target:5′-TGAATGTTGCTGGTGTCTCTCTGAAGA-3′ (SEQ ID NO: 5844)5′-AUGUUGCUGGUGUCUCUCUGAAGac-3′ (SEQ ID NO: 1817)3′-CUUACAACGACCACAGAGAGACUUCUG-5′ (SEQ ID NO: 3831) LDHA-910 Target:5′-GAATGTTGCTGGTGTCTCTCTGAAGAC-3′ (SEQ ID NO: 5845)5′-UGUUGCUGGUGUCUCUCUGAAGAct-3′ (SEQ ID NO: 1818)3′-UUACAACGACCACAGAGAGACUUCUGA-5′ (SEQ ID NO: 3832) LDHA-911 Target:5′-AATGTTGCTGGTGTCTCTCTGAAGACT-3′ (SEQ ID NO: 5846)5′-GUUGCUGGUGUCUCUCUGAAGACtc-3′ (SEQ ID NO: 1819)3′-UACAACGACCACAGAGAGACUUCUGAG-5′ (SEQ ID NO: 3833) LDHA-912 Target:5′-ATGTTGCTGGTGTCTCTCTGAAGACTC-3′ (SEQ ID NO: 5847)5′-UUGCUGGUGUCUCUCUGAAGACUct-3′ (SEQ ID NO: 1820)3′-ACAACGACCACAGAGAGACUUCUGAGA-5′ (SEQ ID NO: 3834) LDHA-913 Target:5′-TGTTGCTGGTGTCTCTCTGAAGACTCT-3′ (SEQ ID NO: 5848)5′-UGCUGGUGUCUCUCUGAAGACUCtg-3′ (SEQ ID NO: 1821)3′-CAACGACCACAGAGAGACUUCUGAGAC-5′ (SEQ ID NO: 3835) LDHA-914 Target:5′-GTTGCTGGTGTCTCTCTGAAGACTCTG-3′ (SEQ ID NO: 5849)5′-GCUGGUGUCUCUCUGAAGACUCUgc-3′ (SEQ ID NO: 1822)3′-AACGACCACAGAGAGACUUCUGAGACG-5′ (SEQ ID NO: 3836) LDHA-915 Target:5′-TTGCTGGTGTCTCTCTGAAGACTCTGC-3′ (SEQ ID NO: 5850)5′-CUGGUGUCUCUCUGAAGACUCUGca-3′ (SEQ ID NO: 1823)3′-ACGACCACAGAGAGACUUCUGAGACGU-5′ (SEQ ID NO: 3837) LDHA-916 Target:5′-TGCTGGTGTCTCTCTGAAGACTCTGCA-3′ (SEQ ID NO: 5851)5′-UGGUGUCUCUCUGAAGACUCUGCac-3′ (SEQ ID NO: 1824)3′-CGACCACAGAGAGACUUCUGAGACGUG-5′ (SEQ ID NO: 3838) LDHA-917 Target:5′-GCTGGTGTCTCTCTGAAGACTCTGCAC-3′ (SEQ ID NO: 5852)5′-GGUGUCUCUCUGAAGACUCUGCAcc-3′ (SEQ ID NO: 1825)3′-GACCACAGAGAGACUUCUGAGACGUGG-5′ (SEQ ID NO: 3839) LDHA-918 Target:5′-CTGGTGTCTCTCTGAAGACTCTGCACC-3′ (SEQ ID NO: 5853)5′-GUGUCUCUCUGAAGACUCUGCACcc-3′ (SEQ ID NO: 1826)3′-ACCACAGAGAGACUUCUGAGACGUGGG-5′ (SEQ ID NO: 3840) LDHA-919 Target:5′-TGGTGTCTCTCTGAAGACTCTGCACCC-3′ (SEQ ID NO: 5854)5′-UGUCUCUCUGAAGACUCUGCACCca-3′ (SEQ ID NO: 1827)3′-CCACAGAGAGACUUCUGAGACGUGGGU-5′ (SEQ ID NO: 3841) LDHA-920 Target:5′-GGTGTCTCTCTGAAGACTCTGCACCCA-3′ (SEQ ID NO: 5855)5′-GUCUCUCUGAAGACUCUGCACCCag-3′ (SEQ ID NO: 1828)3′-CACAGAGAGACUUCUGAGACGUGGGUC-5′ (SEQ ID NO: 3842) LDHA-921 Target:5′-GTGTCTCTCTGAAGACTCTGCACCCAG-3′ (SEQ ID NO: 5856)5′-UCUCUCUGAAGACUCUGCACCCAga-3′ (SEQ ID NO: 1829)3′-ACAGAGAGACUUCUGAGACGUGGGUCU-5′ (SEQ ID NO: 3843) LDHA-922 Target:5′-TGTCTCTCTGAAGACTCTGCACCCAGA-3′ (SEQ ID NO: 5857)5′-CUCUCUGAAGACUCUGCACCCAGat-3′ (SEQ ID NO: 1830)3′-CAGAGAGACUUCUGAGACGUGGGUCUA-5′ (SEQ ID NO: 3844) LDHA-923 Target:5′-GTCTCTCTGAAGACTCTGCACCCAGAT-3′ (SEQ ID NO: 5858)5′-UCUCUGAAGACUCUGCACCCAGAtt-3′ (SEQ ID NO: 1831)3′-AGAGAGACUUCUGAGACGUGGGUCUAA-5′ (SEQ ID NO: 3845) LDHA-924 Target:5′-TCTCTCTGAAGACTCTGCACCCAGATT-3′ (SEQ ID NO: 5859)5′-CUCUGAAGACUCUGCACCCAGAUtt-3′ (SEQ ID NO: 1832)3′-GAGAGACUUCUGAGACGUGGGUCUAAA-5′ (SEQ ID NO: 3846) LDHA-925 Target:5′-CTCTCTGAAGACTCTGCACCCAGATTT-3′ (SEQ ID NO: 5860)5′-UCUGAAGACUCUGCACCCAGAUUta-3′ (SEQ ID NO: 1833)3′-AGAGACUUCUGAGACGUGGGUCUAAAU-5′ (SEQ ID NO: 3847) LDHA-926 Target:5′-TCTCTGAAGACTCTGCACCCAGATTTA-3′ (SEQ ID NO: 5861)5′-CUGAAGACUCUGCACCCAGAUUUag-3′ (SEQ ID NO: 1834)3′-GAGACUUCUGAGACGUGGGUCUAAAUC-5′ (SEQ ID NO: 3848) LDHA-927 Target:5′-CTCTGAAGACTCTGCACCCAGATTTAG-3′ (SEQ ID NO: 5862)5′-UGAAGACUCUGCACCCAGAUUUAgg-3′ (SEQ ID NO: 1835)3′-AGACUUCUGAGACGUGGGUCUAAAUCC-5′ (SEQ ID NO: 3849) LDHA-928 Target:5′-TCTGAAGACTCTGCACCCAGATTTAGG-3′ (SEQ ID NO: 5863)5′-GAAGACUCUGCACCCAGAUUUAGgg-3′ (SEQ ID NO: 1836)3′-GACUUCUGAGACGUGGGUCUAAAUCCC-5′ (SEQ ID NO: 3850) LDHA-929 Target:5′-CTGAAGACTCTGCACCCAGATTTAGGG-3′ (SEQ ID NO: 5864)5′-AAGACUCUGCACCCAGAUUUAGGga-3′ (SEQ ID NO: 1837)3′-ACUUCUGAGACGUGGGUCUAAAUCCCU-5′ (SEQ ID NO: 3851) LDHA-930 Target:5′-TGAAGACTCTGCACCCAGATTTAGGGA-3′ (SEQ ID NO: 5865)5′-AGACUCUGCACCCAGAUUUAGGGac-3′ (SEQ ID NO: 1838)3′-CUUCUGAGACGUGGGUCUAAAUCCCUG-5′ (SEQ ID NO: 3852) LDHA-931 Target:5′-GAAGACTCTGCACCCAGATTTAGGGAC-3′ (SEQ ID NO: 5866)5′-GACUCUGCACCCAGAUUUAGGGAct-3′ (SEQ ID NO: 1839)3′-UUCUGAGACGUGGGUCUAAAUCCCUGA-5′ (SEQ ID NO: 3853) LDHA-932 Target:5′-AAGACTCTGCACCCAGATTTAGGGACT-3′ (SEQ ID NO: 5867)5′-ACUCUGCACCCAGAUUUAGGGACtg-3′ (SEQ ID NO: 1840)3′-UCUGAGACGUGGGUCUAAAUCCCUGAC-5′ (SEQ ID NO: 3854) LDHA-933 Target:5′-AGACTCTGCACCCAGATTTAGGGACTG-3′ (SEQ ID NO: 5868)5′-CUCUGCACCCAGAUUUAGGGACUga-3′ (SEQ ID NO: 1841)3′-CUGAGACGUGGGUCUAAAUCCCUGACU-5′ (SEQ ID NO: 3855) LDHA-934 Target:5′-GACTCTGCACCCAGATTTAGGGACTGA-3′ (SEQ ID NO: 5869)5′-UCUGCACCCAGAUUUAGGGACUGat-3′ (SEQ ID NO: 1842)3′-UGAGACGUGGGUCUAAAUCCCUGACUA-5′ (SEQ ID NO: 3856) LDHA-935 Target:5′-ACTCTGCACCCAGATTTAGGGACTGAT-3′ (SEQ ID NO: 5870)5′-CUGCACCCAGAUUUAGGGACUGAta-3′ (SEQ ID NO: 1843)3′-GAGACGUGGGUCUAAAUCCCUGACUAU-5′ (SEQ ID NO: 3857) LDHA-936 Target:5′-CTCTGCACCCAGATTTAGGGACTGATA-3′ (SEQ ID NO: 5871)5′-UGCACCCAGAUUUAGGGACUGAUaa-3′ (SEQ ID NO: 1844)3′-AGACGUGGGUCUAAAUCCCUGACUAUU-5′ (SEQ ID NO: 3858) LDHA-937 Target:5′-TCTGCACCCAGATTTAGGGACTGATAA-3′ (SEQ ID NO: 5872)5′-GCACCCAGAUUUAGGGACUGAUAaa-3′ (SEQ ID NO: 1845)3′-GACGUGGGUCUAAAUCCCUGACUAUUU-5′ (SEQ ID NO: 3859) LDHA-938 Target:5′-CTGCACCCAGATTTAGGGACTGATAAA-3′ (SEQ ID NO: 5873)5′-CACCCAGAUUUAGGGACUGAUAAag-3′ (SEQ ID NO: 1846)3′-ACGUGGGUCUAAAUCCCUGACUAUUUC-5′ (SEQ ID NO: 3860) LDHA-939 Target:5′-TGCACCCAGATTTAGGGACTGATAAAG-3′ (SEQ ID NO: 5874)5′-ACCCAGAUUUAGGGACUGAUAAAga-3′ (SEQ ID NO: 1847)3′-CGUGGGUCUAAAUCCCUGACUAUUUCU-5′ (SEQ ID NO: 3861) LDHA-940 Target:5′-GCACCCAGATTTAGGGACTGATAAAGA-3′ (SEQ ID NO: 5875)5′-CCCAGAUUUAGGGACUGAUAAAGat-3′ (SEQ ID NO: 1848)3′-GUGGGUCUAAAUCCCUGACUAUUUCUA-5′ (SEQ ID NO: 3862) LDHA-941 Target:5′-CACCCAGATTTAGGGACTGATAAAGAT-3′ (SEQ ID NO: 5876)5′-CCAGAUUUAGGGACUGAUAAAGAta-3′ (SEQ ID NO: 1849)3′-UGGGUCUAAAUCCCUGACUAUUUCUAU-5′ (SEQ ID NO: 3863) LDHA-942 Target:5′-ACCCAGATTTAGGGACTGATAAAGATA-3′ (SEQ ID NO: 5877)5′-CAGAUUUAGGGACUGAUAAAGAUaa-3′ (SEQ ID NO: 1850)3′-GGGUCUAAAUCCCUGACUAUUUCUAUU-5′ (SEQ ID NO: 3864) LDHA-943 Target:5′-CCCAGATTTAGGGACTGATAAAGATAA-3′ (SEQ ID NO: 5878)5′-AGAUUUAGGGACUGAUAAAGAUAag-3′ (SEQ ID NO: 1851)3′-GGUCUAAAUCCCUGACUAUUUCUAUUC-5′ (SEQ ID NO: 3865) LDHA-944 Target:5′-CCAGATTTAGGGACTGATAAAGATAAG-3′ (SEQ ID NO: 5879)5′-GAUUUAGGGACUGAUAAAGAUAAgg-3′ (SEQ ID NO: 1852)3′-GUCUAAAUCCCUGACUAUUUCUAUUCC-5′ (SEQ ID NO: 3866) LDHA-945 Target:5′-CAGATTTAGGGACTGATAAAGATAAGG-3′ (SEQ ID NO: 5880)5′-AUUUAGGGACUGAUAAAGAUAAGga-3′ (SEQ ID NO: 1853)3′-UCUAAAUCCCUGACUAUUUCUAUUCCU-5′ (SEQ ID NO: 3867) LDHA-946 Target:5′-AGATTTAGGGACTGATAAAGATAAGGA-3′ (SEQ ID NO: 5881)5′-UUUAGGGACUGAUAAAGAUAAGGaa-3′ (SEQ ID NO: 1854)3′-CUAAAUCCCUGACUAUUUCUAUUCCUU-5′ (SEQ ID NO: 3868) LDHA-947 Target:5′-GATTTAGGGACTGATAAAGATAAGGAA-3′ (SEQ ID NO: 5882)5′-UUAGGGACUGAUAAAGAUAAGGAac-3′ (SEQ ID NO: 1855)3′-UAAAUCCCUGACUAUUUCUAUUCCUUG-5′ (SEQ ID NO: 3869) LDHA-948 Target:5′-ATTTAGGGACTGATAAAGATAAGGAAC-3′ (SEQ ID NO: 5883)5′-UAGGGACUGAUAAAGAUAAGGAAca-3′ (SEQ ID NO: 1856)3′-AAAUCCCUGACUAUUUCUAUUCCUUGU-5′ (SEQ ID NO: 3870) LDHA-949 Target:5′-TTTAGGGACTGATAAAGATAAGGAACA-3′ (SEQ ID NO: 5884)5′-AGGGACUGAUAAAGAUAAGGAACag-3′ (SEQ ID NO: 1857)3′-AAUCCCUGACUAUUUCUAUUCCUUGUC-5′ (SEQ ID NO: 3871) LDHA-950 Target:5′-TTAGGGACTGATAAAGATAAGGAACAG-3′ (SEQ ID NO: 5885)5′-GGGACUGAUAAAGAUAAGGAACAgt-3′ (SEQ ID NO: 1858)3′-AUCCCUGACUAUUUCUAUUCCUUGUCA-5′ (SEQ ID NO: 3872) LDHA-951 Target:5′-TAGGGACTGATAAAGATAAGGAACAGT-3′ (SEQ ID NO: 5886)5′-GACUGAUAAAGAUAAGGAACAGUgg-3′ (SEQ ID NO: 1859)3′-CCCUGACUAUUUCUAUUCCUUGUCACC-5′ (SEQ ID NO: 3873) LDHA-953 Target:5′-GGGACTGATAAAGATAAGGAACAGTGG-3′ (SEQ ID NO: 5887)5′-ACUGAUAAAGAUAAGGAACAGUGga-3′ (SEQ ID NO: 1860)3′-CCUGACUAUUUCUAUUCCUUGUCACCU-5′ (SEQ ID NO: 3874) LDHA-954 Target:5′-GGACTGATAAAGATAAGGAACAGTGGA-3′ (SEQ ID NO: 5888)5′-CUGAUAAAGAUAAGGAACAGUGGaa-3′ (SEQ ID NO: 1861)3′-CUGACUAUUUCUAUUCCUUGUCACCUU-5′ (SEQ ID NO: 3875) LDHA-955 Target:5′-GACTGATAAAGATAAGGAACAGTGGAA-3′ (SEQ ID NO: 5889)5′-UGAUAAAGAUAAGGAACAGUGGAaa-3′ (SEQ ID NO: 1862)3′-UGACUAUUUCUAUUCCUUGUCACCUUU-5′ (SEQ ID NO: 3876) LDHA-956 Target:5′-ACTGATAAAGATAAGGAACAGTGGAAA-3′ (SEQ ID NO: 5890)5′-GAUAAAGAUAAGGAACAGUGGAAag-3′ (SEQ ID NO: 1863)3′-GACUAUUUCUAUUCCUUGUCACCUUUC-5′ (SEQ ID NO: 3877) LDHA-957 Target:5′-CTGATAAAGATAAGGAACAGTGGAAAG-3′ (SEQ ID NO: 5891)5′-AUAAAGAUAAGGAACAGUGGAAAga-3′ (SEQ ID NO: 1864)3′-ACUAUUUCUAUUCCUUGUCACCUUUCU-5′ (SEQ ID NO: 3878) LDHA-958 Target:5′-TGATAAAGATAAGGAACAGTGGAAAGA-3′ (SEQ ID NO: 5892)5′-UAAAGAUAAGGAACAGUGGAAAGag-3′ (SEQ ID NO: 1865)3′-CUAUUUCUAUUCCUUGUCACCUUUCUC-5′ (SEQ ID NO: 3879) LDHA-959 Target:5′-GATAAAGATAAGGAACAGTGGAAAGAG-3′ (SEQ ID NO: 5893)5′-AAAGAUAAGGAACAGUGGAAAGAgg-3′ (SEQ ID NO: 1866)3′-UAUUUCUAUUCCUUGUCACCUUUCUCC-5′ (SEQ ID NO: 3880) LDHA-960 Target:5′-ATAAAGATAAGGAACAGTGGAAAGAGG-3′ (SEQ ID NO: 5894)5′-AAGAUAAGGAACAGUGGAAAGAGgt-3′ (SEQ ID NO: 1867)3′-AUUUCUAUUCCUUGUCACCUUUCUCCA-5′ (SEQ ID NO: 3881) LDHA-961 Target:5′-TAAAGATAAGGAACAGTGGAAAGAGGT-3′ (SEQ ID NO: 5895)5′-AGAUAAGGAACAGUGGAAAGAGGtt-3′ (SEQ ID NO: 1868)3′-UUUCUAUUCCUUGUCACCUUUCUCCAA-5′ (SEQ ID NO: 3882) LDHA-962 Target:5′-AAAGATAAGGAACAGTGGAAAGAGGTT-3′ (SEQ ID NO: 5896)5′-GAUAAGGAACAGUGGAAAGAGGUtc-3′ (SEQ ID NO: 1869)3′-UUCUAUUCCUUGUCACCUUUCUCCAAG-5′ (SEQ ID NO: 3883) LDHA-963 Target:5′-AAGATAAGGAACAGTGGAAAGAGGTTC-3′ (SEQ ID NO: 5897)5′-AUAAGGAACAGUGGAAAGAGGUUca-3′ (SEQ ID NO: 1870)3′-UCUAUUCCUUGUCACCUUUCUCCAAGU-5′ (SEQ ID NO: 3884) LDHA-964 Target:5′-AGATAAGGAACAGTGGAAAGAGGTTCA-3′ (SEQ ID NO: 5898)5′-UAAGGAACAGUGGAAAGAGGUUCac-3′ (SEQ ID NO: 1871)3′-CUAUUCCUUGUCACCUUUCUCCAAGUG-5′ (SEQ ID NO: 3885) LDHA-965 Target:5′-GATAAGGAACAGTGGAAAGAGGTTCAC-3′ (SEQ ID NO: 5899)5′-AAGGAACAGUGGAAAGAGGUUCAca-3′ (SEQ ID NO: 1872)3′-UAUUCCUUGUCACCUUUCUCCAAGUGU-5′ (SEQ ID NO: 3886) LDHA-966 Target:5′-ATAAGGAACAGTGGAAAGAGGTTCACA-3′ (SEQ ID NO: 5900)5′-AGGAACAGUGGAAAGAGGUUCACaa-3′ (SEQ ID NO: 1873)3′-AUUCCUUGUCACCUUUCUCCAAGUGUU-5′ (SEQ ID NO: 3887) LDHA-967 Target:5′-TAAGGAACAGTGGAAAGAGGTTCACAA-3′ (SEQ ID NO: 5901)5′-GGAACAGUGGAAAGAGGUUCACAag-3′ (SEQ ID NO: 1874)3′-UUCCUUGUCACCUUUCUCCAAGUGUUC-5′ (SEQ ID NO: 3888) LDHA-968 Target:5′-AAGGAACAGTGGAAAGAGGTTCACAAG-3′ (SEQ ID NO: 5902)5′-GAACAGUGGAAAGAGGUUCACAAgc-3′ (SEQ ID NO: 1875)3′-UCCUUGUCACCUUUCUCCAAGUGUUCG-5′ (SEQ ID NO: 3889) LDHA-969 Target:5′-AGGAACAGTGGAAAGAGGTTCACAAGC-3′ (SEQ ID NO: 5903)5′-AACAGUGGAAAGAGGUUCACAAGca-3′ (SEQ ID NO: 1876)3′-CCUUGUCACCUUUCUCCAAGUGUUCGU-5′ (SEQ ID NO: 3890) LDHA-970 Target:5′-GGAACAGTGGAAAGAGGTTCACAAGCA-3′ (SEQ ID NO: 5904)5′-ACAGUGGAAAGAGGUUCACAAGCag-3′ (SEQ ID NO: 1877)3′-CUUGUCACCUUUCUCCAAGUGUUCGUC-5′ (SEQ ID NO: 3891) LDHA-971 Target:5′-GAACAGTGGAAAGAGGTTCACAAGCAG-3′ (SEQ ID NO: 5905)5′-CAGUGGAAAGAGGUUCACAAGCAgg-3′ (SEQ ID NO: 1878)3′-UUGUCACCUUUCUCCAAGUGUUCGUCC-5′ (SEQ ID NO: 3892) LDHA-972 Target:5′-AACAGTGGAAAGAGGTTCACAAGCAGG-3′ (SEQ ID NO: 5906)5′-AGUGGAAAGAGGUUCACAAGCAGgt-3′ (SEQ ID NO: 1879)3′-UGUCACCUUUCUCCAAGUGUUCGUCCA-5′ (SEQ ID NO: 3893) LDHA-973 Target:5′-ACAGTGGAAAGAGGTTCACAAGCAGGT-3′ (SEQ ID NO: 5907)5′-GUGGAAAGAGGUUCACAAGCAGGtg-3′ (SEQ ID NO: 1880)3′-GUCACCUUUCUCCAAGUGUUCGUCCAC-5′ (SEQ ID NO: 3894) LDHA-974 Target:5′-CAGTGGAAAGAGGTTCACAAGCAGGTG-3′ (SEQ ID NO: 5908)5′-UGGAAAGAGGUUCACAAGCAGGUgg-3′ (SEQ ID NO: 1881)3′-UCACCUUUCUCCAAGUGUUCGUCCACC-5′ (SEQ ID NO: 3895) LDHA-975 Target:5′-AGTGGAAAGAGGTTCACAAGCAGGTGG-3′ (SEQ ID NO: 5909)5′-GGAAAGAGGUUCACAAGCAGGUGgt-3′ (SEQ ID NO: 1882)3′-CACCUUUCUCCAAGUGUUCGUCCACCA-5′ (SEQ ID NO: 3896) LDHA-976 Target:5′-GTGGAAAGAGGTTCACAAGCAGGTGGT-3′ (SEQ ID NO: 5910)5′-GAAAGAGGUUCACAAGCAGGUGGtt-3′ (SEQ ID NO: 1883)3′-ACCUUUCUCCAAGUGUUCGUCCACCAA-5′ (SEQ ID NO: 3897) LDHA-977 Target:5′-TGGAAAGAGGTTCACAAGCAGGTGGTT-3′ (SEQ ID NO: 5911)5′-AAAGAGGUUCACAAGCAGGUGGUtg-3′ (SEQ ID NO: 1884)3′-CCUUUCUCCAAGUGUUCGUCCACCAAC-5′ (SEQ ID NO: 3898) LDHA-978 Target:5′-GGAAAGAGGTTCACAAGCAGGTGGTTG-3′ (SEQ ID NO: 5912)5′-AAGAGGUUCACAAGCAGGUGGUUga-3′ (SEQ ID NO: 1885)3′-CUUUCUCCAAGUGUUCGUCCACCAACU-5′ (SEQ ID NO: 3899) LDHA-979 Target:5′-GAAAGAGGTTCACAAGCAGGTGGTTGA-3′ (SEQ ID NO: 5913)5′-AGAGGUUCACAAGCAGGUGGUUGag-3′ (SEQ ID NO: 1886)3′-UUUCUCCAAGUGUUCGUCCACCAACUC-5′ (SEQ ID NO: 3900) LDHA-980 Target:5′-AAAGAGGTTCACAAGCAGGTGGTTGAG-3′ (SEQ ID NO: 5914)5′-GAGGUUCACAAGCAGGUGGUUGAga-3′ (SEQ ID NO: 1887)3′-UUCUCCAAGUGUUCGUCCACCAACUCU-5′ (SEQ ID NO: 3901) LDHA-981 Target:5′-AAGAGGTTCACAAGCAGGTGGTTGAGA-3′ (SEQ ID NO: 5915)5′-AGGUUCACAAGCAGGUGGUUGAGag-3′ (SEQ ID NO: 1888)3′-UCUCCAAGUGUUCGUCCACCAACUCUC-5′ (SEQ ID NO: 3902) LDHA-982 Target:5′-AGAGGTTCACAAGCAGGTGGTTGAGAG-3′ (SEQ ID NO: 5916)5′-GGUUCACAAGCAGGUGGUUGAGAgt-3′ (SEQ ID NO: 1889)3′-CUCCAAGUGUUCGUCCACCAACUCUCA-5′ (SEQ ID NO: 3903) LDHA-983 Target:5′-GAGGTTCACAAGCAGGTGGTTGAGAGT-3′ (SEQ ID NO: 5917)5′-GUUCACAAGCAGGUGGUUGAGAGtg-3′ (SEQ ID NO: 1890)3′-UCCAAGUGUUCGUCCACCAACUCUCAC-5′ (SEQ ID NO: 3904) LDHA-984 Target:5′-AGGTTCACAAGCAGGTGGTTGAGAGTG-3′ (SEQ ID NO: 5918)5′-UUCACAAGCAGGUGGUUGAGAGUgc-3′ (SEQ ID NO: 1891)3′-CCAAGUGUUCGUCCACCAACUCUCACG-5′ (SEQ ID NO: 3905) LDHA-985 Target:5′-GGTTCACAAGCAGGTGGTTGAGAGTGC-3′ (SEQ ID NO: 5919)5′-UCACAAGCAGGUGGUUGAGAGUGct-3′ (SEQ ID NO: 1892)3′-CAAGUGUUCGUCCACCAACUCUCACGA-5′ (SEQ ID NO: 3906) LDHA-986 Target:5′-GTTCACAAGCAGGTGGTTGAGAGTGCT-3′ (SEQ ID NO: 5920)5′-CACAAGCAGGUGGUUGAGAGUGCtt-3′ (SEQ ID NO: 1893)3′-AAGUGUUCGUCCACCAACUCUCACGAA-5′ (SEQ ID NO: 3907) LDHA-987 Target:5′-TTCACAAGCAGGTGGTTGAGAGTGCTT-3′ (SEQ ID NO: 5921)5′-ACAAGCAGGUGGUUGAGAGUGCUta-3′ (SEQ ID NO: 1894)3′-AGUGUUCGUCCACCAACUCUCACGAAU-5′ (SEQ ID NO: 3908) LDHA-988 Target:5′-TCACAAGCAGGTGGTTGAGAGTGCTTA-3′ (SEQ ID NO: 5922)5′-CAAGCAGGUGGUUGAGAGUGCUUat-3′ (SEQ ID NO: 1895)3′-GUGUUCGUCCACCAACUCUCACGAAUA-5′ (SEQ ID NO: 3909) LDHA-989 Target:5′-CACAAGCAGGTGGTTGAGAGTGCTTAT-3′ (SEQ ID NO: 5923)5′-AAGCAGGUGGUUGAGAGUGCUUAtg-3′ (SEQ ID NO: 1896)3′-UGUUCGUCCACCAACUCUCACGAAUAC-5′ (SEQ ID NO: 3910) LDHA-990 Target:5′-ACAAGCAGGTGGTTGAGAGTGCTTATG-3′ (SEQ ID NO: 5924)5′-AGCAGGUGGUUGAGAGUGCUUAUga-3′ (SEQ ID NO: 1897)3′-GUUCGUCCACCAACUCUCACGAAUACU-5′ (SEQ ID NO: 3911) LDHA-991 Target:5′-CAAGCAGGTGGTTGAGAGTGCTTATGA-3′ (SEQ ID NO: 5925)5′-GCAGGUGGUUGAGAGUGCUUAUGag-3′ (SEQ ID NO: 1898)3′-UUCGUCCACCAACUCUCACGAAUACUC-5′ (SEQ ID NO: 3912) LDHA-992 Target:5′-AAGCAGGTGGTTGAGAGTGCTTATGAG-3′ (SEQ ID NO: 5926)5′-CAGGUGGUUGAGAGUGCUUAUGAgg-3′ (SEQ ID NO: 1899)3′-UCGUCCACCAACUCUCACGAAUACUCC-5′ (SEQ ID NO: 3913) LDHA-993 Target:5′-AGCAGGTGGTTGAGAGTGCTTATGAGG-3′ (SEQ ID NO: 5927)5′-AGGUGGUUGAGAGUGCUUAUGAGgt-3′ (SEQ ID NO: 1900)3′-CGUCCACCAACUCUCACGAAUACUCCA-5′ (SEQ ID NO: 3914) LDHA-994 Target:5′-GCAGGTGGTTGAGAGTGCTTATGAGGT-3′ (SEQ ID NO: 5928)5′-GGUGGUUGAGAGUGCUUAUGAGGtg-3′ (SEQ ID NO: 1901)3′-GUCCACCAACUCUCACGAAUACUCCAC-5′ (SEQ ID NO: 3915) LDHA-995 Target:5′-CAGGTGGTTGAGAGTGCTTATGAGGTG-3′ (SEQ ID NO: 5929)5′-GUGGUUGAGAGUGCUUAUGAGGUga-3′ (SEQ ID NO: 1902)3′-UCCACCAACUCUCACGAAUACUCCACU-5′ (SEQ ID NO: 3916) LDHA-996 Target:5′-AGGTGGTTGAGAGTGCTTATGAGGTGA-3′ (SEQ ID NO: 5930)5′-UGGUUGAGAGUGCUUAUGAGGUGat-3′ (SEQ ID NO: 1903)3′-CCACCAACUCUCACGAAUACUCCACUA-5′ (SEQ ID NO: 3917) LDHA-997 Target:5′-GGTGGTTGAGAGTGCTTATGAGGTGAT-3′ (SEQ ID NO: 5931)5′-GGUUGAGAGUGCUUAUGAGGUGAtc-3′ (SEQ ID NO: 1904)3′-CACCAACUCUCACGAAUACUCCACUAG-5′ (SEQ ID NO: 3918) LDHA-998 Target:5′-GTGGTTGAGAGTGCTTATGAGGTGATC-3′ (SEQ ID NO: 5932)5′-GUUGAGAGUGCUUAUGAGGUGAUca-3′ (SEQ ID NO: 1905)3′-ACCAACUCUCACGAAUACUCCACUAGU-5′ (SEQ ID NO: 3919) LDHA-999 Target:5′-TGGTTGAGAGTGCTTATGAGGTGATCA-3′ (SEQ ID NO: 5933)5′-UUGAGAGUGCUUAUGAGGUGAUCaa-3′ (SEQ ID NO: 1906)3′-CCAACUCUCACGAAUACUCCACUAGUU-5′ (SEQ ID NO: 3920) LDHA-1000 Target:5′-GGTTGAGAGTGCTTATGAGGTGATCAA-3′ (SEQ ID NO: 5934)5′-UGAGAGUGCUUAUGAGGUGAUCAaa-3′ (SEQ ID NO: 1907)3′-CAACUCUCACGAAUACUCCACUAGUUU-5′ (SEQ ID NO: 3921) LDHA-1001 Target:5′-GTTGAGAGTGCTTATGAGGTGATCAAA-3′ (SEQ ID NO: 5935)5′-GAGAGUGCUUAUGAGGUGAUCAAac-3′ (SEQ ID NO: 1908)3′-AACUCUCACGAAUACUCCACUAGUUUG-5′ (SEQ ID NO: 3922) LDHA-1002 Target:5′-TTGAGAGTGCTTATGAGGTGATCAAAC-3′ (SEQ ID NO: 5936)5′-AGAGUGCUUAUGAGGUGAUCAAAct-3′ (SEQ ID NO: 1909)3′-ACUCUCACGAAUACUCCACUAGUUUGA-5′ (SEQ ID NO: 3923) LDHA-1003 Target:5′-TGAGAGTGCTTATGAGGTGATCAAACT-3′ (SEQ ID NO: 5937)5′-GAGUGCUUAUGAGGUGAUCAAACtc-3′ (SEQ ID NO: 1910)3′-CUCUCACGAAUACUCCACUAGUUUGAG-5′ (SEQ ID NO: 3924) LDHA-1004 Target:5′-GAGAGTGCTTATGAGGTGATCAAACTC-3′ (SEQ ID NO: 5938)5′-AGUGCUUAUGAGGUGAUCAAACUca-3′ (SEQ ID NO: 1911)3′-UCUCACGAAUACUCCACUAGUUUGAGU-5′ (SEQ ID NO: 3925) LDHA-1005 Target:5′-AGAGTGCTTATGAGGTGATCAAACTCA-3′ (SEQ ID NO: 5939)5′-GUGCUUAUGAGGUGAUCAAACUCaa-3′ (SEQ ID NO: 1912)3′-CUCACGAAUACUCCACUAGUUUGAGUU-5′ (SEQ ID NO: 3926) LDHA-1006 Target:5′-GAGTGCTTATGAGGTGATCAAACTCAA-3′ (SEQ ID NO: 5940)5′-UGCUUAUGAGGUGAUCAAACUCAaa-3′ (SEQ ID NO: 1913)3′-UCACGAAUACUCCACUAGUUUGAGUUU-5′ (SEQ ID NO: 3927) LDHA-1007 Target:5′-AGTGCTTATGAGGTGATCAAACTCAAA-3′ (SEQ ID NO: 5941)5′-GCUUAUGAGGUGAUCAAACUCAAag-3′ (SEQ ID NO: 1914)3′-CACGAAUACUCCACUAGUUUGAGUUUC-5′ (SEQ ID NO: 3928) LDHA-1008 Target:5′-GTGCTTATGAGGTGATCAAACTCAAAG-3′ (SEQ ID NO: 5942)5′-CUUAUGAGGUGAUCAAACUCAAAgg-3′ (SEQ ID NO: 1915)3′-ACGAAUACUCCACUAGUUUGAGUUUCC-5′ (SEQ ID NO: 3929) LDHA-1009 Target:5′-TGCTTATGAGGTGATCAAACTCAAAGG-3′ (SEQ ID NO: 5943)5′-UUAUGAGGUGAUCAAACUCAAAGgc-3′ (SEQ ID NO: 1916)3′-CGAAUACUCCACUAGUUUGAGUUUCCG-5′ (SEQ ID NO: 3930) LDHA-1010 Target:5′-GCTTATGAGGTGATCAAACTCAAAGGC-3′ (SEQ ID NO: 5944)5′-UAUGAGGUGAUCAAACUCAAAGGct-3′ (SEQ ID NO: 1917)3′-GAAUACUCCACUAGUUUGAGUUUCCGA-5′ (SEQ ID NO: 3931) LDHA-1011 Target:5′-CTTATGAGGTGATCAAACTCAAAGGCT-3′ (SEQ ID NO: 5945)5′-AUGAGGUGAUCAAACUCAAAGGCta-3′ (SEQ ID NO: 1918)3′-AAUACUCCACUAGUUUGAGUUUCCGAU-5′ (SEQ ID NO: 3932) LDHA-1012 Target:5′-TTATGAGGTGATCAAACTCAAAGGCTA-3′ (SEQ ID NO: 5946)5′-UGAGGUGAUCAAACUCAAAGGCUac-3′ (SEQ ID NO: 1919)3′-AUACUCCACUAGUUUGAGUUUCCGAUG-5′ (SEQ ID NO: 3933) LDHA-1013 Target:5′-TATGAGGTGATCAAACTCAAAGGCTAC-3′ (SEQ ID NO: 5947)5′-GAGGUGAUCAAACUCAAAGGCUAca-3′ (SEQ ID NO: 1920)3′-UACUCCACUAGUUUGAGUUUCCGAUGU-5′ (SEQ ID NO: 3934) LDHA-1014 Target:5′-ATGAGGTGATCAAACTCAAAGGCTACA-3′ (SEQ ID NO: 5948)5′-AGGUGAUCAAACUCAAAGGCUACac-3′ (SEQ ID NO: 1921)3′-ACUCCACUAGUUUGAGUUUCCGAUGUG-5′ (SEQ ID NO: 3935) LDHA-1015 Target:5′-TGAGGTGATCAAACTCAAAGGCTACAC-3′ (SEQ ID NO: 5949)5′-GGUGAUCAAACUCAAAGGCUACAca-3′ (SEQ ID NO: 1922)3′-CUCCACUAGUUUGAGUUUCCGAUGUGU-5′ (SEQ ID NO: 3936) LDHA-1016 Target:5′-GAGGTGATCAAACTCAAAGGCTACACA-3′ (SEQ ID NO: 5950)5′-GUGAUCAAACUCAAAGGCUACACat-3′ (SEQ ID NO: 1923)3′-UCCACUAGUUUGAGUUUCCGAUGUGUA-5′ (SEQ ID NO: 3937) LDHA-1017 Target:5′-AGGTGATCAAACTCAAAGGCTACACAT-3′ (SEQ ID NO: 5951)5′-UGAUCAAACUCAAAGGCUACACAtc-3′ (SEQ ID NO: 1924)3′-CCACUAGUUUGAGUUUCCGAUGUGUAG-5′ (SEQ ID NO: 3938) LDHA-1018 Target:5′-GGTGATCAAACTCAAAGGCTACACATC-3′ (SEQ ID NO: 5952)5′-GAUCAAACUCAAAGGCUACACAUcc-3′ (SEQ ID NO: 1925)3′-CACUAGUUUGAGUUUCCGAUGUGUAGG-5′ (SEQ ID NO: 3939) LDHA-1019 Target:5′-GTGATCAAACTCAAAGGCTACACATCC-3′ (SEQ ID NO: 5953)5′-AUCAAACUCAAAGGCUACACAUCct-3′ (SEQ ID NO: 1926)3′-ACUAGUUUGAGUUUCCGAUGUGUAGGA-5′ (SEQ ID NO: 3940) LDHA-1020 Target:5′-TGATCAAACTCAAAGGCTACACATCCT-3′ (SEQ ID NO: 5954)5′-UCAAACUCAAAGGCUACACAUCCtg-3′ (SEQ ID NO: 1927)3′-CUAGUUUGAGUUUCCGAUGUGUAGGAC-5′ (SEQ ID NO: 3941) LDHA-1021 Target:5′-GATCAAACTCAAAGGCTACACATCCTG-3′ (SEQ ID NO: 5955)5′-CAAACUCAAAGGCUACACAUCCUgg-3′ (SEQ ID NO: 1928)3′-UAGUUUGAGUUUCCGAUGUGUAGGACC-5′ (SEQ ID NO: 3942) LDHA-1022 Target:5′-ATCAAACTCAAAGGCTACACATCCTGG-3′ (SEQ ID NO: 5956)5′-AAACUCAAAGGCUACACAUCCUGgg-3′ (SEQ ID NO: 1929)3′-AGUUUGAGUUUCCGAUGUGUAGGACCC-5′ (SEQ ID NO: 3943) LDHA-1023 Target:5′-TCAAACTCAAAGGCTACACATCCTGGG-3′ (SEQ ID NO: 5957)5′-AACUCAAAGGCUACACAUCCUGGgc-3′ (SEQ ID NO: 1930)3′-GUUUGAGUUUCCGAUGUGUAGGACCCG-5′ (SEQ ID NO: 3944) LDHA-1024 Target:5′-CAAACTCAAAGGCTACACATCCTGGGC-3′ (SEQ ID NO: 5958)5′-ACUCAAAGGCUACACAUCCUGGGct-3′ (SEQ ID NO: 1931)3′-UUUGAGUUUCCGAUGUGUAGGACCCGA-5′ (SEQ ID NO: 3945) LDHA-1025 Target:5′-AAACTCAAAGGCTACACATCCTGGGCT-3′ (SEQ ID NO: 5959)5′-CUCAAAGGCUACACAUCCUGGGCta-3′ (SEQ ID NO: 1932)3′-UUGAGUUUCCGAUGUGUAGGACCCGAU-5′ (SEQ ID NO: 3946) LDHA-1026 Target:5′-AACTCAAAGGCTACACATCCTGGGCTA-3′ (SEQ ID NO: 5960)5′-UCAAAGGCUACACAUCCUGGGCUat-3′ (SEQ ID NO: 1933)3′-UGAGUUUCCGAUGUGUAGGACCCGAUA-5′ (SEQ ID NO: 3947) LDHA-1027 Target:5′-ACTCAAAGGCTACACATCCTGGGCTAT-3′ (SEQ ID NO: 5961)5′-CAAAGGCUACACAUCCUGGGCUAtt-3′ (SEQ ID NO: 1934)3′-GAGUUUCCGAUGUGUAGGACCCGAUAA-5′ (SEQ ID NO: 3948) LDHA-1028 Target:5′-CTCAAAGGCTACACATCCTGGGCTATT-3′ (SEQ ID NO: 5962)5′-AAAGGCUACACAUCCUGGGCUAUtg-3′ (SEQ ID NO: 1935)3′-AGUUUCCGAUGUGUAGGACCCGAUAAC-5′ (SEQ ID NO: 3949) LDHA-1029 Target:5′-TCAAAGGCTACACATCCTGGGCTATTG-3′ (SEQ ID NO: 5963)5′-AAGGCUACACAUCCUGGGCUAUUgg-3′ (SEQ ID NO: 1936)3′-GUUUCCGAUGUGUAGGACCCGAUAACC-5′ (SEQ ID NO: 3950) LDHA-1030 Target:5′-CAAAGGCTACACATCCTGGGCTATTGG-3′ (SEQ ID NO: 5964)5′-AGGCUACACAUCCUGGGCUAUUGga-3′ (SEQ ID NO: 1937)3′-UUUCCGAUGUGUAGGACCCGAUAACCU-5′ (SEQ ID NO: 3951) LDHA-1031 Target:5′-AAAGGCTACACATCCTGGGCTATTGGA-3′ (SEQ ID NO: 5965)5′-GGCUACACAUCCUGGGCUAUUGGac-3′ (SEQ ID NO: 1938)3′-UUCCGAUGUGUAGGACCCGAUAACCUG-5′ (SEQ ID NO: 3952) LDHA-1032 Target:5′-AAGGCTACACATCCTGGGCTATTGGAC-3′ (SEQ ID NO: 5966)5′-GCUACACAUCCUGGGCUAUUGGAct-3′ (SEQ ID NO: 1939)3′-UCCGAUGUGUAGGACCCGAUAACCUGA-5′ (SEQ ID NO: 3953) LDHA-1033 Target:5′-AGGCTACACATCCTGGGCTATTGGACT-3′ (SEQ ID NO: 5967)5′-CUACACAUCCUGGGCUAUUGGACtc-3′ (SEQ ID NO: 1940)3′-CCGAUGUGUAGGACCCGAUAACCUGAG-5′ (SEQ ID NO: 3954) LDHA-1034 Target:5′-GGCTACACATCCTGGGCTATTGGACTC-3′ (SEQ ID NO: 5968)5′-UACACAUCCUGGGCUAUUGGACUct-3′ (SEQ ID NO: 1941)3′-CGAUGUGUAGGACCCGAUAACCUGAGA-5′ (SEQ ID NO: 3955) LDHA-1035 Target:5′-GCTACACATCCTGGGCTATTGGACTCT-3′ (SEQ ID NO: 5969)5′-ACACAUCCUGGGCUAUUGGACUCtc-3′ (SEQ ID NO: 1942)3′-GAUGUGUAGGACCCGAUAACCUGAGAG-5′ (SEQ ID NO: 3956) LDHA-1036 Target:5′-CTACACATCCTGGGCTATTGGACTCTC-3′ (SEQ ID NO: 5970)5′-CACAUCCUGGGCUAUUGGACUCUct-3′ (SEQ ID NO: 1943)3′-AUGUGUAGGACCCGAUAACCUGAGAGA-5′ (SEQ ID NO: 3957) LDHA-1037 Target:5′-TACACATCCTGGGCTATTGGACTCTCT-3′ (SEQ ID NO: 5971)5′-ACAUCCUGGGCUAUUGGACUCUCtg-3′ (SEQ ID NO: 1944)3′-UGUGUAGGACCCGAUAACCUGAGAGAC-5′ (SEQ ID NO: 3958) LDHA-1038 Target:5′-ACACATCCTGGGCTATTGGACTCTCTG-3′ (SEQ ID NO: 5972)5′-CAUCCUGGGCUAUUGGACUCUCUgt-3′ (SEQ ID NO: 1945)3′-GUGUAGGACCCGAUAACCUGAGAGACA-5′ (SEQ ID NO: 3959) LDHA-1039 Target:5′-CACATCCTGGGCTATTGGACTCTCTGT-3′ (SEQ ID NO: 5973)5′-AUCCUGGGCUAUUGGACUCUCUGta-3′ (SEQ ID NO: 1946)3′-UGUAGGACCCGAUAACCUGAGAGACAU-5′ (SEQ ID NO: 3960) LDHA-1040 Target:5′-ACATCCTGGGCTATTGGACTCTCTGTA-3′ (SEQ ID NO: 5974)5′-UCCUGGGCUAUUGGACUCUCUGUag-3′ (SEQ ID NO: 1947)3′-GUAGGACCCGAUAACCUGAGAGACAUC-5′ (SEQ ID NO: 3961) LDHA-1041 Target:5′-CATCCTGGGCTATTGGACTCTCTGTAG-3′ (SEQ ID NO: 5975)5′-CCUGGGCUAUUGGACUCUCUGUAgc-3′ (SEQ ID NO: 1948)3′-UAGGACCCGAUAACCUGAGAGACAUCG-5′ (SEQ ID NO: 3962) LDHA-1042 Target:5′-ATCCTGGGCTATTGGACTCTCTGTAGC-3′ (SEQ ID NO: 5976)5′-CUGGGCUAUUGGACUCUCUGUAGca-3′ (SEQ ID NO: 1949)3′-AGGACCCGAUAACCUGAGAGACAUCGU-5′ (SEQ ID NO: 3963) LDHA-1043 Target:5′-TCCTGGGCTATTGGACTCTCTGTAGCA-3′ (SEQ ID NO: 5977)5′-UGGGCUAUUGGACUCUCUGUAGCag-3′ (SEQ ID NO: 1950)3′-GGACCCGAUAACCUGAGAGACAUCGUC-5′ (SEQ ID NO: 3964) LDHA-1044 Target:5′-CCTGGGCTATTGGACTCTCTGTAGCAG-3′ (SEQ ID NO: 5978)5′-GGGCUAUUGGACUCUCUGUAGCAga-3′ (SEQ ID NO: 1951)3′-GACCCGAUAACCUGAGAGACAUCGUCU-5′ (SEQ ID NO: 3965) LDHA-1045 Target:5′-CTGGGCTATTGGACTCTCTGTAGCAGA-3′ (SEQ ID NO: 5979)5′-GGCUAUUGGACUCUCUGUAGCAGat-3′ (SEQ ID NO: 1952)3′-ACCCGAUAACCUGAGAGACAUCGUCUA-5′ (SEQ ID NO: 3966) LDHA-1046 Target:5′-TGGGCTATTGGACTCTCTGTAGCAGAT-3′ (SEQ ID NO: 5980)5′-GCUAUUGGACUCUCUGUAGCAGAtt-3′ (SEQ ID NO: 1953)3′-CCCGAUAACCUGAGAGACAUCGUCUAA-5′ (SEQ ID NO: 3967) LDHA-1047 Target:5′-GGGCTATTGGACTCTCTGTAGCAGATT-3′ (SEQ ID NO: 5981)5′-CUAUUGGACUCUCUGUAGCAGAUtt-3′ (SEQ ID NO: 1954)3′-CCGAUAACCUGAGAGACAUCGUCUAAA-5′ (SEQ ID NO: 3968) LDHA-1048 Target:5′-GGCTATTGGACTCTCTGTAGCAGATTT-3′ (SEQ ID NO: 5982)5′-UAUUGGACUCUCUGUAGCAGAUUtg-3′ (SEQ ID NO: 1955)3′-CGAUAACCUGAGAGACAUCGUCUAAAC-5′ (SEQ ID NO: 3969) LDHA-1049 Target:5′-GCTATTGGACTCTCTGTAGCAGATTTG-3′ (SEQ ID NO: 5983)5′-AUUGGACUCUCUGUAGCAGAUUUgg-3′ (SEQ ID NO: 1956)3′-GAUAACCUGAGAGACAUCGUCUAAACC-5′ (SEQ ID NO: 3970) LDHA-1050 Target:5′-CTATTGGACTCTCTGTAGCAGATTTGG-3′ (SEQ ID NO: 5984)5′-UUGGACUCUCUGUAGCAGAUUUGgc-3′ (SEQ ID NO: 1957)3′-AUAACCUGAGAGACAUCGUCUAAACCG-5′ (SEQ ID NO: 3971) LDHA-1051 Target:5′-TATTGGACTCTCTGTAGCAGATTTGGC-3′ (SEQ ID NO: 5985)5′-UGGACUCUCUGUAGCAGAUUUGGca-3′ (SEQ ID NO: 1958)3′-UAACCUGAGAGACAUCGUCUAAACCGU-5′ (SEQ ID NO: 3972) LDHA-1052 Target:5′-ATTGGACTCTCTGTAGCAGATTTGGCA-3′ (SEQ ID NO: 5986)5′-GGACUCUCUGUAGCAGAUUUGGCag-3′ (SEQ ID NO: 1959)3′-AACCUGAGAGACAUCGUCUAAACCGUC-5′ (SEQ ID NO: 3973) LDHA-1053 Target:5′-TTGGACTCTCTGTAGCAGATTTGGCAG-3′ (SEQ ID NO: 5987)5′-GACUCUCUGUAGCAGAUUUGGCAga-3′ (SEQ ID NO: 1960)3′-ACCUGAGAGACAUCGUCUAAACCGUCU-5′ (SEQ ID NO: 3974) LDHA-1054 Target:5′-TGGACTCTCTGTAGCAGATTTGGCAGA-3′ (SEQ ID NO: 5988)5′-ACUCUCUGUAGCAGAUUUGGCAGag-3′ (SEQ ID NO: 1961)3′-CCUGAGAGACAUCGUCUAAACCGUCUC-5′ (SEQ ID NO: 3975) LDHA-1055 Target:5′-GGACTCTCTGTAGCAGATTTGGCAGAG-3′ (SEQ ID NO: 5989)5′-CUCUCUGUAGCAGAUUUGGCAGAga-3′ (SEQ ID NO: 1962)3′-CUGAGAGACAUCGUCUAAACCGUCUCU-5′ (SEQ ID NO: 3976) LDHA-1056 Target:5′-GACTCTCTGTAGCAGATTTGGCAGAGA-3′ (SEQ ID NO: 5990)5′-UCUCUGUAGCAGAUUUGGCAGAGag-3′ (SEQ ID NO: 1963)3′-UGAGAGACAUCGUCUAAACCGUCUCUC-5′ (SEQ ID NO: 3977) LDHA-1057 Target:5′-ACTCTCTGTAGCAGATTTGGCAGAGAG-3′ (SEQ ID NO: 5991)5′-CUCUGUAGCAGAUUUGGCAGAGAgt-3′ (SEQ ID NO: 1964)3′-GAGAGACAUCGUCUAAACCGUCUCUCA-5′ (SEQ ID NO: 3978) LDHA-1058 Target:5′-CTCTCTGTAGCAGATTTGGCAGAGAGT-3′ (SEQ ID NO: 5992)5′-UCUGUAGCAGAUUUGGCAGAGAGta-3′ (SEQ ID NO: 1965)3′-AGAGACAUCGUCUAAACCGUCUCUCAU-5′ (SEQ ID NO: 3979) LDHA-1059 Target:5′-TCTCTGTAGCAGATTTGGCAGAGAGTA-3′ (SEQ ID NO: 5993)5′-CUGUAGCAGAUUUGGCAGAGAGUat-3′ (SEQ ID NO: 1966)3′-GAGACAUCGUCUAAACCGUCUCUCAUA-5′ (SEQ ID NO: 3980) LDHA-1060 Target:5′-CTCTGTAGCAGATTTGGCAGAGAGTAT-3′ (SEQ ID NO: 5994)5′-UGUAGCAGAUUUGGCAGAGAGUAta-3′ (SEQ ID NO: 1967)3′-AGACAUCGUCUAAACCGUCUCUCAUAU-5′ (SEQ ID NO: 3981) LDHA-1061 Target:5′-TCTGTAGCAGATTTGGCAGAGAGTATA-3′ (SEQ ID NO: 5995)5′-GUAGCAGAUUUGGCAGAGAGUAUaa-3′ (SEQ ID NO: 1968)3′-GACAUCGUCUAAACCGUCUCUCAUAUU-5′ (SEQ ID NO: 3982) LDHA-1062 Target:5′-CTGTAGCAGATTTGGCAGAGAGTATAA-3′ (SEQ ID NO: 5996)5′-UAGCAGAUUUGGCAGAGAGUAUAat-3′ (SEQ ID NO: 1969)3′-ACAUCGUCUAAACCGUCUCUCAUAUUA-5′ (SEQ ID NO: 3983) LDHA-1063 Target:5′-TGTAGCAGATTTGGCAGAGAGTATAAT-3′ (SEQ ID NO: 5997)5′-AGCAGAUUUGGCAGAGAGUAUAAtg-3′ (SEQ ID NO: 1970)3′-CAUCGUCUAAACCGUCUCUCAUAUUAC-5′ (SEQ ID NO: 3984) LDHA-1064 Target:5′-GTAGCAGATTTGGCAGAGAGTATAATG-3′ (SEQ ID NO: 5998)5′-GCAGAUUUGGCAGAGAGUAUAAUga-3′ (SEQ ID NO: 1971)3′-AUCGUCUAAACCGUCUCUCAUAUUACU-5′ (SEQ ID NO: 3985) LDHA-1065 Target:5′-TAGCAGATTTGGCAGAGAGTATAATGA-3′ (SEQ ID NO: 5999)5′-CAGAUUUGGCAGAGAGUAUAAUGaa-3′ (SEQ ID NO: 1972)3′-UCGUCUAAACCGUCUCUCAUAUUACUU-5′ (SEQ ID NO: 3986) LDHA-1066 Target:5′-AGCAGATTTGGCAGAGAGTATAATGAA-3′ (SEQ ID NO: 6000)5′-AGAUUUGGCAGAGAGUAUAAUGAag-3′ (SEQ ID NO: 1973)3′-CGUCUAAACCGUCUCUCAUAUUACUUC-5′ (SEQ ID NO: 3987) LDHA-1067 Target:5′-GCAGATTTGGCAGAGAGTATAATGAAG-3′ (SEQ ID NO: 6001)5′-GAUUUGGCAGAGAGUAUAAUGAAga-3′ (SEQ ID NO: 1974)3′-GUCUAAACCGUCUCUCAUAUUACUUCU-5′ (SEQ ID NO: 3988) LDHA-1068 Target:5′-CAGATTTGGCAGAGAGTATAATGAAGA-3′ (SEQ ID NO: 6002)5′-AUUUGGCAGAGAGUAUAAUGAAGaa-3′ (SEQ ID NO: 1975)3′-UCUAAACCGUCUCUCAUAUUACUUCUU-5′ (SEQ ID NO: 3989) LDHA-1069 Target:5′-AGATTTGGCAGAGAGTATAATGAAGAA-3′ (SEQ ID NO: 6003)5′-UUUGGCAGAGAGUAUAAUGAAGAat-3′ (SEQ ID NO: 1976)3′-CUAAACCGUCUCUCAUAUUACUUCUUA-5′ (SEQ ID NO: 3990) LDHA-1070 Target:5′-GATTTGGCAGAGAGTATAATGAAGAAT-3′ (SEQ ID NO: 6004)5′-UUGGCAGAGAGUAUAAUGAAGAAtc-3′ (SEQ ID NO: 1977)3′-UAAACCGUCUCUCAUAUUACUUCUUAG-5′ (SEQ ID NO: 3991) LDHA-1071 Target:5′-ATTTGGCAGAGAGTATAATGAAGAATC-3′ (SEQ ID NO: 6005)5′-UGGCAGAGAGUAUAAUGAAGAAUct-3′ (SEQ ID NO: 1978)3′-AAACCGUCUCUCAUAUUACUUCUUAGA-5′ (SEQ ID NO: 3992) LDHA-1072 Target:5′-TTTGGCAGAGAGTATAATGAAGAATCT-3′ (SEQ ID NO: 6006)5′-GGCAGAGAGUAUAAUGAAGAAUCtt-3′ (SEQ ID NO: 1979)3′-AACCGUCUCUCAUAUUACUUCUUAGAA-5′ (SEQ ID NO: 3993) LDHA-1073 Target:5′-TTGGCAGAGAGTATAATGAAGAATCTT-3′ (SEQ ID NO: 6007)5′-GCAGAGAGUAUAAUGAAGAAUCUta-3′ (SEQ ID NO: 1980)3′-ACCGUCUCUCAUAUUACUUCUUAGAAU-5′ (SEQ ID NO: 3994) LDHA-1074 Target:5′-TGGCAGAGAGTATAATGAAGAATCTTA-3′ (SEQ ID NO: 6008)5′-CAGAGAGUAUAAUGAAGAAUCUUag-3′ (SEQ ID NO: 1981)3′-CCGUCUCUCAUAUUACUUCUUAGAAUC-5′ (SEQ ID NO: 3995) LDHA-1075 Target:5′-GGCAGAGAGTATAATGAAGAATCTTAG-3′ (SEQ ID NO: 6009)5′-AGAGAGUAUAAUGAAGAAUCUUAgg-3′ (SEQ ID NO: 1982)3′-CGUCUCUCAUAUUACUUCUUAGAAUCC-5′ (SEQ ID NO: 3996) LDHA-1076 Target:5′-GCAGAGAGTATAATGAAGAATCTTAGG-3′ (SEQ ID NO: 6010)5′-GAGAGUAUAAUGAAGAAUCUUAGgc-3′ (SEQ ID NO: 1983)3′-GUCUCUCAUAUUACUUCUUAGAAUCCG-5′ (SEQ ID NO: 3997) LDHA-1077 Target:5′-CAGAGAGTATAATGAAGAATCTTAGGC-3′ (SEQ ID NO: 6011)5′-AGAGUAUAAUGAAGAAUCUUAGGcg-3′ (SEQ ID NO: 1984)3′-UCUCUCAUAUUACUUCUUAGAAUCCGC-5′ (SEQ ID NO: 3998) LDHA-1078 Target:5′-AGAGAGTATAATGAAGAATCTTAGGCG-3′ (SEQ ID NO: 6012)5′-GAGUAUAAUGAAGAAUCUUAGGCgg-3′ (SEQ ID NO: 1985)3′-CUCUCAUAUUACUUCUUAGAAUCCGCC-5′ (SEQ ID NO: 3999) LDHA-1079 Target:5′-GAGAGTATAATGAAGAATCTTAGGCGG-3′ (SEQ ID NO: 6013)5′-AGUAUAAUGAAGAAUCUUAGGCGgg-3′ (SEQ ID NO: 1986)3′-UCUCAUAUUACUUCUUAGAAUCCGCCC-5′ (SEQ ID NO: 4000) LDHA-1080 Target:5′-AGAGTATAATGAAGAATCTTAGGCGGG-3′ (SEQ ID NO: 6014)5′-GUAUAAUGAAGAAUCUUAGGCGGgt-3′ (SEQ ID NO: 1987)3′-CUCAUAUUACUUCUUAGAAUCCGCCCA-5′ (SEQ ID NO: 4001) LDHA-1081 Target:5′-GAGTATAATGAAGAATCTTAGGCGGGT-3′ (SEQ ID NO: 6015)5′-UAUAAUGAAGAAUCUUAGGCGGGtg-3′ (SEQ ID NO: 1988)3′-UCAUAUUACUUCUUAGAAUCCGCCCAC-5′ (SEQ ID NO: 4002) LDHA-1082 Target:5′-AGTATAATGAAGAATCTTAGGCGGGTG-3′ (SEQ ID NO: 6016)5′-AUAAUGAAGAAUCUUAGGCGGGUgc-3′ (SEQ ID NO: 1989)3′-CAUAUUACUUCUUAGAAUCCGCCCACG-5′ (SEQ ID NO: 4003) LDHA-1083 Target:5′-GTATAATGAAGAATCTTAGGCGGGTGC-3′ (SEQ ID NO: 6017)5′-UAAUGAAGAAUCUUAGGCGGGUGca-3′ (SEQ ID NO: 1990)3′-AUAUUACUUCUUAGAAUCCGCCCACGU-5′ (SEQ ID NO: 4004) LDHA-1084 Target:5′-TATAATGAAGAATCTTAGGCGGGTGCA-3′ (SEQ ID NO: 6018)5′-AAUGAAGAAUCUUAGGCGGGUGCac-3′ (SEQ ID NO: 1991)3′-UAUUACUUCUUAGAAUCCGCCCACGUG-5′ (SEQ ID NO: 4005) LDHA-1085 Target:5′-ATAATGAAGAATCTTAGGCGGGTGCAC-3′ (SEQ ID NO: 6019)5′-AUGAAGAAUCUUAGGCGGGUGCAcc-3′ (SEQ ID NO: 1992)3′-AUUACUUCUUAGAAUCCGCCCACGUGG-5′ (SEQ ID NO: 4006) LDHA-1086 Target:5′-TAATGAAGAATCTTAGGCGGGTGCACC-3′ (SEQ ID NO: 6020)5′-UGAAGAAUCUUAGGCGGGUGCACcc-3′ (SEQ ID NO: 1993)3′-UUACUUCUUAGAAUCCGCCCACGUGGG-5′ (SEQ ID NO: 4007) LDHA-1087 Target:5′-AATGAAGAATCTTAGGCGGGTGCACCC-3′ (SEQ ID NO: 6021)5′-GAAGAAUCUUAGGCGGGUGCACCca-3′ (SEQ ID NO: 1994)3′-UACUUCUUAGAAUCCGCCCACGUGGGU-5′ (SEQ ID NO: 4008) LDHA-1088 Target:5′-ATGAAGAATCTTAGGCGGGTGCACCCA-3′ (SEQ ID NO: 6022)5′-AAGAAUCUUAGGCGGGUGCACCCag-3′ (SEQ ID NO: 1995)3′-ACUUCUUAGAAUCCGCCCACGUGGGUC-5′ (SEQ ID NO: 4009) LDHA-1089 Target:5′-TGAAGAATCTTAGGCGGGTGCACCCAG-3′ (SEQ ID NO: 6023)5′-AGAAUCUUAGGCGGGUGCACCCAgt-3′ (SEQ ID NO: 1996)3′-CUUCUUAGAAUCCGCCCACGUGGGUCA-5′ (SEQ ID NO: 4010) LDHA-1090 Target:5′-GAAGAATCTTAGGCGGGTGCACCCAGT-3′ (SEQ ID NO: 6024)5′-GAAUCUUAGGCGGGUGCACCCAGtt-3′ (SEQ ID NO: 1997)3′-UUCUUAGAAUCCGCCCACGUGGGUCAA-5′ (SEQ ID NO: 4011) LDHA-1091 Target:5′-AAGAATCTTAGGCGGGTGCACCCAGTT-3′ (SEQ ID NO: 6025)5′-AAUCUUAGGCGGGUGCACCCAGUtt-3′ (SEQ ID NO: 1998)3′-UCUUAGAAUCCGCCCACGUGGGUCAAA-5′ (SEQ ID NO: 4012) LDHA-1092 Target:5′-AGAATCTTAGGCGGGTGCACCCAGTTT-3′ (SEQ ID NO: 6026)5′-AUCUUAGGCGGGUGCACCCAGUUtc-3′ (SEQ ID NO: 1999)3′-CUUAGAAUCCGCCCACGUGGGUCAAAG-5′ (SEQ ID NO: 4013) LDHA-1093 Target:5′-GAATCTTAGGCGGGTGCACCCAGTTTC-3′ (SEQ ID NO: 6027)5′-UCUUAGGCGGGUGCACCCAGUUUcc-3′ (SEQ ID NO: 2000)3′-UUAGAAUCCGCCCACGUGGGUCAAAGG-5′ (SEQ ID NO: 4014) LDHA-1094 Target:5′-AATCTTAGGCGGGTGCACCCAGTTTCC-3′ (SEQ ID NO: 6028)5′-CUUAGGCGGGUGCACCCAGUUUCca-3′ (SEQ ID NO: 2001)3′-UAGAAUCCGCCCACGUGGGUCAAAGGU-5′ (SEQ ID NO: 4015) LDHA-1095 Target:5′-ATCTTAGGCGGGTGCACCCAGTTTCCA-3′ (SEQ ID NO: 6029)5′-UUAGGCGGGUGCACCCAGUUUCCac-3′ (SEQ ID NO: 2002)3′-AGAAUCCGCCCACGUGGGUCAAAGGUG-5′ (SEQ ID NO: 4016) LDHA-1096 Target:5′-TCTTAGGCGGGTGCACCCAGTTTCCAC-3′ (SEQ ID NO: 6030)5′-UAGGCGGGUGCACCCAGUUUCCAcc-3′ (SEQ ID NO: 2003)3′-GAAUCCGCCCACGUGGGUCAAAGGUGG-5′ (SEQ ID NO: 4017) LDHA-1097 Target:5′-CTTAGGCGGGTGCACCCAGTTTCCACC-3′ (SEQ ID NO: 6031)5′-AGGCGGGUGCACCCAGUUUCCACca-3′ (SEQ ID NO: 2004)3′-AAUCCGCCCACGUGGGUCAAAGGUGGU-5′ (SEQ ID NO: 4018) LDHA-1098 Target:5′-TTAGGCGGGTGCACCCAGTTTCCACCA-3′ (SEQ ID NO: 6032)5′-GGCGGGUGCACCCAGUUUCCACCat-3′ (SEQ ID NO: 2005)3′-AUCCGCCCACGUGGGUCAAAGGUGGUA-5′ (SEQ ID NO: 4019) LDHA-1099 Target:5′-TAGGCGGGTGCACCCAGTTTCCACCAT-3′ (SEQ ID NO: 6033)5′-GCGGGUGCACCCAGUUUCCACCAtg-3′ (SEQ ID NO: 2006)3′-UCCGCCCACGUGGGUCAAAGGUGGUAC-5′ (SEQ ID NO: 4020) LDHA-1100 Target:5′-AGGCGGGTGCACCCAGTTTCCACCATG-3′ (SEQ ID NO: 6034)5′-CGGGUGCACCCAGUUUCCACCAUga-3′ (SEQ ID NO: 2007)3′-CCGCCCACGUGGGUCAAAGGUGGUACU-5′ (SEQ ID NO: 4021) LDHA-1101 Target:5′-GGCGGGTGCACCCAGTTTCCACCATGA-3′ (SEQ ID NO: 6035)5′-GGGUGCACCCAGUUUCCACCAUGat-3′ (SEQ ID NO: 2008)3′-CGCCCACGUGGGUCAAAGGUGGUACUA-5′ (SEQ ID NO: 4022) LDHA-1102 Target:5′-GCGGGTGCACCCAGTTTCCACCATGAT-3′ (SEQ ID NO: 6036)5′-GGUGCACCCAGUUUCCACCAUGAtt-3′ (SEQ ID NO: 2009)3′-GCCCACGUGGGUCAAAGGUGGUACUAA-5′ (SEQ ID NO: 4023) LDHA-1103 Target:5′-CGGGTGCACCCAGTTTCCACCATGATT-3′ (SEQ ID NO: 6037)5′-GUGCACCCAGUUUCCACCAUGAUta-3′ (SEQ ID NO: 2010)3′-CCCACGUGGGUCAAAGGUGGUACUAAU-5′ (SEQ ID NO: 4024) LDHA-1104 Target:5′-GGGTGCACCCAGTTTCCACCATGATTA-3′ (SEQ ID NO: 6038)5′-UGCACCCAGUUUCCACCAUGAUUaa-3′ (SEQ ID NO: 2011)3′-CCACGUGGGUCAAAGGUGGUACUAAUU-5′ (SEQ ID NO: 4025) LDHA-1105 Target:5′-GGTGCACCCAGTTTCCACCATGATTAA-3′ (SEQ ID NO: 6039)5′-GCACCCAGUUUCCACCAUGAUUAag-3′ (SEQ ID NO: 2012)3′-CACGUGGGUCAAAGGUGGUACUAAUUC-5′ (SEQ ID NO: 4026) LDHA-1106 Target:5′-GTGCACCCAGTTTCCACCATGATTAAG-3′ (SEQ ID NO: 6040)5′-CACCCAGUUUCCACCAUGAUUAAgg-3′ (SEQ ID NO: 2013)3′-ACGUGGGUCAAAGGUGGUACUAAUUCC-5′ (SEQ ID NO: 4027) LDHA-1107 Target:5′-TGCACCCAGTTTCCACCATGATTAAGG-3′ (SEQ ID NO: 6041)5′-ACCCAGUUUCCACCAUGAUUAAGgg-3′ (SEQ ID NO: 2014)3′-CGUGGGUCAAAGGUGGUACUAAUUCCC-5′ (SEQ ID NO: 4028) LDHA-1108 Target:5′-GCACCCAGTTTCCACCATGATTAAGGG-3′ (SEQ ID NO: 6042)5′-CCCAGUUUCCACCAUGAUUAAGGgt-3′ (SEQ ID NO: 2015)3′-GUGGGUCAAAGGUGGUACUAAUUCCCA-5′ (SEQ ID NO: 4029) LDHA-1109 Target:5′-CACCCAGTTTCCACCATGATTAAGGGT-3′ (SEQ ID NO: 6043)5′-CCAGUUUCCACCAUGAUUAAGGGtc-3′ (SEQ ID NO: 2016)3′-UGGGUCAAAGGUGGUACUAAUUCCCAG-5′ (SEQ ID NO: 4030) LDHA-1110 Target:5′-ACCCAGTTTCCACCATGATTAAGGGTC-3′ (SEQ ID NO: 6044)5′-CAGUUUCCACCAUGAUUAAGGGUct-3′ (SEQ ID NO: 2017)3′-GGGUCAAAGGUGGUACUAAUUCCCAGA-5′ (SEQ ID NO: 4031) LDHA-1111 Target:5′-CCCAGTTTCCACCATGATTAAGGGTCT-3′ (SEQ ID NO: 6045)5′-AGUUUCCACCAUGAUUAAGGGUCtt-3′ (SEQ ID NO: 2018)3′-GGUCAAAGGUGGUACUAAUUCCCAGAA-5′ (SEQ ID NO: 4032) LDHA-1112 Target:5′-CCAGTTTCCACCATGATTAAGGGTCTT-3′ (SEQ ID NO: 6046)5′-GUUUCCACCAUGAUUAAGGGUCUtt-3′ (SEQ ID NO: 2019)3′-GUCAAAGGUGGUACUAAUUCCCAGAAA-5′ (SEQ ID NO: 4033) LDHA-1113 Target:5′-CAGTTTCCACCATGATTAAGGGTCTTT-3′ (SEQ ID NO: 6047)5′-UUUCCACCAUGAUUAAGGGUCUUta-3′ (SEQ ID NO: 2020)3′-UCAAAGGUGGUACUAAUUCCCAGAAAU-5′ (SEQ ID NO: 4034) LDHA-1114 Target:5′-AGTTTCCACCATGATTAAGGGTCTTTA-3′ (SEQ ID NO: 6048)5′-UUCCACCAUGAUUAAGGGUCUUUac-3′ (SEQ ID NO: 2021)3′-CAAAGGUGGUACUAAUUCCCAGAAAUG-5′ (SEQ ID NO: 4035) LDHA-1115 Target:5′-GTTTCCACCATGATTAAGGGTCTTTAC-3′ (SEQ ID NO: 6049)5′-UCCACCAUGAUUAAGGGUCUUUAcg-3′ (SEQ ID NO: 2022)3′-AAAGGUGGUACUAAUUCCCAGAAAUGC-5′ (SEQ ID NO: 4036) LDHA-1116 Target:5′-TTTCCACCATGATTAAGGGTCTTTACG-3′ (SEQ ID NO: 6050)5′-CCACCAUGAUUAAGGGUCUUUACgg-3′ (SEQ ID NO: 2023)3′-AAGGUGGUACUAAUUCCCAGAAAUGCC-5′ (SEQ ID NO: 4037) LDHA-1117 Target:5′-TTCCACCATGATTAAGGGTCTTTACGG-3′ (SEQ ID NO: 6051)5′-CACCAUGAUUAAGGGUCUUUACGga-3′ (SEQ ID NO: 2024)3′-AGGUGGUACUAAUUCCCAGAAAUGCCU-5′ (SEQ ID NO: 4038) LDHA-1118 Target:5′-TCCACCATGATTAAGGGTCTTTACGGA-3′ (SEQ ID NO: 6052)5′-ACCAUGAUUAAGGGUCUUUACGGaa-3′ (SEQ ID NO: 2025)3′-GGUGGUACUAAUUCCCAGAAAUGCCUU-5′ (SEQ ID NO: 4039) LDHA-1119 Target:5′-CCACCATGATTAAGGGTCTTTACGGAA-3′ (SEQ ID NO: 6053)5′-CCAUGAUUAAGGGUCUUUACGGAat-3′ (SEQ ID NO: 2026)3′-GUGGUACUAAUUCCCAGAAAUGCCUUA-5′ (SEQ ID NO: 4040) LDHA-1120 Target:5′-CACCATGATTAAGGGTCTTTACGGAAT-3′ (SEQ ID NO: 6054)5′-CAUGAUUAAGGGUCUUUACGGAAta-3′ (SEQ ID NO: 2027)3′-UGGUACUAAUUCCCAGAAAUGCCUUAU-5′ (SEQ ID NO: 4041) LDHA-1121 Target:5′-ACCATGATTAAGGGTCTTTACGGAATA-3′ (SEQ ID NO: 6055)5′-AUGAUUAAGGGUCUUUACGGAAUaa-3′ (SEQ ID NO: 2028)3′-GGUACUAAUUCCCAGAAAUGCCUUAUU-5′ (SEQ ID NO: 4042) LDHA-1122 Target:5′-CCATGATTAAGGGTCTTTACGGAATAA-3′ (SEQ ID NO: 6056)5′-UGAUUAAGGGUCUUUACGGAAUAaa-3′ (SEQ ID NO: 2029)3′-GUACUAAUUCCCAGAAAUGCCUUAUUU-5′ (SEQ ID NO: 4043) LDHA-1123 Target:5′-CATGATTAAGGGTCTTTACGGAATAAA-3′ (SEQ ID NO: 6057)5′-GAUUAAGGGUCUUUACGGAAUAAag-3′ (SEQ ID NO: 2030)3′-UACUAAUUCCCAGAAAUGCCUUAUUUC-5′ (SEQ ID NO: 4044) LDHA-1124 Target:5′-ATGATTAAGGGTCTTTACGGAATAAAG-3′ (SEQ ID NO: 6058)5′-AUUAAGGGUCUUUACGGAAUAAAgg-3′ (SEQ ID NO: 2031)3′-ACUAAUUCCCAGAAAUGCCUUAUUUCC-5′ (SEQ ID NO: 4045) LDHA-1125 Target:5′-TGATTAAGGGTCTTTACGGAATAAAGG-3′ (SEQ ID NO: 6059)5′-UUAAGGGUCUUUACGGAAUAAAGga-3′ (SEQ ID NO: 2032)3′-CUAAUUCCCAGAAAUGCCUUAUUUCCU-5′ (SEQ ID NO: 4046) LDHA-1126 Target:5′-GATTAAGGGTCTTTACGGAATAAAGGA-3′ (SEQ ID NO: 6060)5′-UAAGGGUCUUUACGGAAUAAAGGat-3′ (SEQ ID NO: 2033)3′-UAAUUCCCAGAAAUGCCUUAUUUCCUA-5′ (SEQ ID NO: 4047) LDHA-1127 Target:5′-ATTAAGGGTCTTTACGGAATAAAGGAT-3′ (SEQ ID NO: 6061)5′-AAGGGUCUUUACGGAAUAAAGGAtg-3′ (SEQ ID NO: 2034)3′-AAUUCCCAGAAAUGCCUUAUUUCCUAC-5′ (SEQ ID NO: 4048) LDHA-1128 Target:5′-TTAAGGGTCTTTACGGAATAAAGGATG-3′ (SEQ ID NO: 6062)5′-AGGGUCUUUACGGAAUAAAGGAUga-3′ (SEQ ID NO: 2035)3′-AUUCCCAGAAAUGCCUUAUUUCCUACU-5′ (SEQ ID NO: 4049) LDHA-1129 Target:5′-TAAGGGTCTTTACGGAATAAAGGATGA-3′ (SEQ ID NO: 6063)5′-GGGUCUUUACGGAAUAAAGGAUGat-3′ (SEQ ID NO: 2036)3′-UUCCCAGAAAUGCCUUAUUUCCUACUA-5′ (SEQ ID NO: 4050) LDHA-1130 Target:5′-AAGGGTCTTTACGGAATAAAGGATGAT-3′ (SEQ ID NO: 6064)5′-GGUCUUUACGGAAUAAAGGAUGAtg-3′ (SEQ ID NO: 2037)3′-UCCCAGAAAUGCCUUAUUUCCUACUAC-5′ (SEQ ID NO: 4051) LDHA-1131 Target:5′-AGGGTCTTTACGGAATAAAGGATGATG-3′ (SEQ ID NO: 6065)5′-GUCUUUACGGAAUAAAGGAUGAUgt-3′ (SEQ ID NO: 2038)3′-CCCAGAAAUGCCUUAUUUCCUACUACA-5′ (SEQ ID NO: 4052) LDHA-1132 Target:5′-GGGTCTTTACGGAATAAAGGATGATGT-3′ (SEQ ID NO: 6066)5′-UCUUUACGGAAUAAAGGAUGAUGtc-3′ (SEQ ID NO: 2039)3′-CCAGAAAUGCCUUAUUUCCUACUACAG-5′ (SEQ ID NO: 4053) LDHA-1133 Target:5′-GGTCTTTACGGAATAAAGGATGATGTC-3′ (SEQ ID NO: 6067)5′-CUUUACGGAAUAAAGGAUGAUGUct-3′ (SEQ ID NO: 2040)3′-CAGAAAUGCCUUAUUUCCUACUACAGA-5′ (SEQ ID NO: 4054) LDHA-1134 Target:5′-GTCTTTACGGAATAAAGGATGATGTCT-3′ (SEQ ID NO: 6068)5′-UUUACGGAAUAAAGGAUGAUGUCtt-3′ (SEQ ID NO: 2041)3′-AGAAAUGCCUUAUUUCCUACUACAGAA-5′ (SEQ ID NO: 4055) LDHA-1135 Target:5′-TCTTTACGGAATAAAGGATGATGTCTT-3′ (SEQ ID NO: 6069)5′-UUACGGAAUAAAGGAUGAUGUCUtc-3′ (SEQ ID NO: 2042)3′-GAAAUGCCUUAUUUCCUACUACAGAAG-5′ (SEQ ID NO: 4056) LDHA-1136 Target:5′-CTTTACGGAATAAAGGATGATGTCTTC-3′ (SEQ ID NO: 6070)5′-UACGGAAUAAAGGAUGAUGUCUUcc-3′ (SEQ ID NO: 2043)3′-AAAUGCCUUAUUUCCUACUACAGAAGG-5′ (SEQ ID NO: 4057) LDHA-1137 Target:5′-TTTACGGAATAAAGGATGATGTCTTCC-3′ (SEQ ID NO: 6071)5′-ACGGAAUAAAGGAUGAUGUCUUCct-3′ (SEQ ID NO: 2044)3′-AAUGCCUUAUUUCCUACUACAGAAGGA-5′ (SEQ ID NO: 4058) LDHA-1138 Target:5′-TTACGGAATAAAGGATGATGTCTTCCT-3′ (SEQ ID NO: 6072)5′-CGGAAUAAAGGAUGAUGUCUUCCtt-3′ (SEQ ID NO: 2045)3′-AUGCCUUAUUUCCUACUACAGAAGGAA-5′ (SEQ ID NO: 4059) LDHA-1139 Target:5′-TACGGAATAAAGGATGATGTCTTCCTT-3′ (SEQ ID NO: 6073)5′-GGAAUAAAGGAUGAUGUCUUCCUta-3′ (SEQ ID NO: 2046)3′-UGCCUUAUUUCCUACUACAGAAGGAAU-5′ (SEQ ID NO: 4060) LDHA-1140 Target:5′-ACGGAATAAAGGATGATGTCTTCCTTA-3′ (SEQ ID NO: 6074)5′-GAAUAAAGGAUGAUGUCUUCCUUag-3′ (SEQ ID NO: 2047)3′-GCCUUAUUUCCUACUACAGAAGGAAUC-5′ (SEQ ID NO: 4061) LDHA-1141 Target:5′-CGGAATAAAGGATGATGTCTTCCTTAG-3′ (SEQ ID NO: 6075)5′-AAUAAAGGAUGAUGUCUUCCUUAgt-3′ (SEQ ID NO: 2048)3′-CCUUAUUUCCUACUACAGAAGGAAUCA-5′ (SEQ ID NO: 4062) LDHA-1142 Target:5′-GGAATAAAGGATGATGTCTTCCTTAGT-3′ (SEQ ID NO: 6076)5′-AUAAAGGAUGAUGUCUUCCUUAGtg-3′ (SEQ ID NO: 2049)3′-CUUAUUUCCUACUACAGAAGGAAUCAC-5′ (SEQ ID NO: 4063) LDHA-1143 Target:5′-GAATAAAGGATGATGTCTTCCTTAGTG-3′ (SEQ ID NO: 6077)5′-UAAAGGAUGAUGUCUUCCUUAGUgt-3′ (SEQ ID NO: 2050)3′-UUAUUUCCUACUACAGAAGGAAUCACA-5′ (SEQ ID NO: 4064) LDHA-1144 Target:5′-AATAAAGGATGATGTCTTCCTTAGTGT-3′ (SEQ ID NO: 6078)5′-AAAGGAUGAUGUCUUCCUUAGUGtt-3′ (SEQ ID NO: 2051)3′-UAUUUCCUACUACAGAAGGAAUCACAA-5′ (SEQ ID NO: 4065) LDHA-1145 Target:5′-ATAAAGGATGATGTCTTCCTTAGTGTT-3′ (SEQ ID NO: 6079)5′-AAGGAUGAUGUCUUCCUUAGUGUtc-3′ (SEQ ID NO: 2052)3′-AUUUCCUACUACAGAAGGAAUCACAAG-5′ (SEQ ID NO: 4066) LDHA-1146 Target:5′-TAAAGGATGATGTCTTCCTTAGTGTTC-3′ (SEQ ID NO: 6080)5′-AGGAUGAUGUCUUCCUUAGUGUUcc-3′ (SEQ ID NO: 2053)3′-UUUCCUACUACAGAAGGAAUCACAAGG-5′ (SEQ ID NO: 4067) LDHA-1147 Target:5′-AAAGGATGATGTCTTCCTTAGTGTTCC-3′ (SEQ ID NO: 6081)5′-GGAUGAUGUCUUCCUUAGUGUUCct-3′ (SEQ ID NO: 2054)3′-UUCCUACUACAGAAGGAAUCACAAGGA-5′ (SEQ ID NO: 4068) LDHA-1148 Target:5′-AAGGATGATGTCTTCCTTAGTGTTCCT-3′ (SEQ ID NO: 6082)5′-GAUGAUGUCUUCCUUAGUGUUCCtt-3′ (SEQ ID NO: 2055)3′-UCCUACUACAGAAGGAAUCACAAGGAA-5′ (SEQ ID NO: 4069) LDHA-1149 Target:5′-AGGATGATGTCTTCCTTAGTGTTCCTT-3′ (SEQ ID NO: 6083)5′-AUGAUGUCUUCCUUAGUGUUCCUtg-3′ (SEQ ID NO: 2056)3′-CCUACUACAGAAGGAAUCACAAGGAAC-5′ (SEQ ID NO: 4070) LDHA-1150 Target:5′-GGATGATGTCTTCCTTAGTGTTCCTTG-3′ (SEQ ID NO: 6084)5′-UGAUGUCUUCCUUAGUGUUCCUUgc-3′ (SEQ ID NO: 2057)3′-CUACUACAGAAGGAAUCACAAGGAACG-5′ (SEQ ID NO: 4071) LDHA-1151 Target:5′-GATGATGTCTTCCTTAGTGTTCCTTGC-3′ (SEQ ID NO: 6085)5′-GAUGUCUUCCUUAGUGUUCCUUGca-3′ (SEQ ID NO: 2058)3′-UACUACAGAAGGAAUCACAAGGAACGU-5′ (SEQ ID NO: 4072) LDHA-1152 Target:5′-ATGATGTCTTCCTTAGTGTTCCTTGCA-3′ (SEQ ID NO: 6086)5′-AUGUCUUCCUUAGUGUUCCUUGCat-3′ (SEQ ID NO: 2059)3′-ACUACAGAAGGAAUCACAAGGAACGUA-5′ (SEQ ID NO: 4073) LDHA-1153 Target:5′-TGATGTCTTCCTTAGTGTTCCTTGCAT-3′ (SEQ ID NO: 6087)5′-UGUCUUCCUUAGUGUUCCUUGCAtt-3′ (SEQ ID NO: 2060)3′-CUACAGAAGGAAUCACAAGGAACGUAA-5′ (SEQ ID NO: 4074) LDHA-1154 Target:5′-GATGTCTTCCTTAGTGTTCCTTGCATT-3′ (SEQ ID NO: 6088)5′-GUCUUCCUUAGUGUUCCUUGCAUtt-3′ (SEQ ID NO: 2061)3′-UACAGAAGGAAUCACAAGGAACGUAAA-5′ (SEQ ID NO: 4075) LDHA-1155 Target:5′-ATGTCTTCCTTAGTGTTCCTTGCATTT-3′ (SEQ ID NO: 6089)5′-UCUUCCUUAGUGUUCCUUGCAUUtt-3′ (SEQ ID NO: 2062)3′-ACAGAAGGAAUCACAAGGAACGUAAAA-5′ (SEQ ID NO: 4076) LDHA-1156 Target:5′-TGTCTTCCTTAGTGTTCCTTGCATTTT-3′ (SEQ ID NO: 6090)5′-CUUCCUUAGUGUUCCUUGCAUUUtg-3′ (SEQ ID NO: 2063)3′-CAGAAGGAAUCACAAGGAACGUAAAAC-5′ (SEQ ID NO: 4077) LDHA-1157 Target:5′-GTCTTCCTTAGTGTTCCTTGCATTTTG-3′ (SEQ ID NO: 6091)5′-UUCCUUAGUGUUCCUUGCAUUUUgg-3′ (SEQ ID NO: 2064)3′-AGAAGGAAUCACAAGGAACGUAAAACC-5′ (SEQ ID NO: 4078) LDHA-1158 Target:5′-TCTTCCTTAGTGTTCCTTGCATTTTGG-3′ (SEQ ID NO: 6092)5′-UCCUUAGUGUUCCUUGCAUUUUGgg-3′ (SEQ ID NO: 2065)3′-GAAGGAAUCACAAGGAACGUAAAACCC-5′ (SEQ ID NO: 4079) LDHA-1159 Target:5′-CTTCCTTAGTGTTCCTTGCATTTTGGG-3′ (SEQ ID NO: 6093)5′-CCUUAGUGUUCCUUGCAUUUUGGga-3′ (SEQ ID NO: 2066)3′-AAGGAAUCACAAGGAACGUAAAACCCU-5′ (SEQ ID NO: 4080) LDHA-1160 Target:5′-TTCCTTAGTGTTCCTTGCATTTTGGGA-3′ (SEQ ID NO: 6094)5′-CUUAGUGUUCCUUGCAUUUUGGGac-3′ (SEQ ID NO: 2067)3′-AGGAAUCACAAGGAACGUAAAACCCUG-5′ (SEQ ID NO: 4081) LDHA-1161 Target:5′-TCCTTAGTGTTCCTTGCATTTTGGGAC-3′ (SEQ ID NO: 6095)5′-UUAGUGUUCCUUGCAUUUUGGGAca-3′ (SEQ ID NO: 2068)3′-GGAAUCACAAGGAACGUAAAACCCUGU-5′ (SEQ ID NO: 4082) LDHA-1162 Target:5′-CCTTAGTGTTCCTTGCATTTTGGGACA-3′ (SEQ ID NO: 6096)5′-UAGUGUUCCUUGCAUUUUGGGACag-3′ (SEQ ID NO: 2069)3′-GAAUCACAAGGAACGUAAAACCCUGUC-5′ (SEQ ID NO: 4083) LDHA-1163 Target:5′-CTTAGTGTTCCTTGCATTTTGGGACAG-3′ (SEQ ID NO: 6097)5′-AGUGUUCCUUGCAUUUUGGGACAga-3′ (SEQ ID NO: 2070)3′-AAUCACAAGGAACGUAAAACCCUGUCU-5′ (SEQ ID NO: 4084) LDHA-1164 Target:5′-TTAGTGTTCCTTGCATTTTGGGACAGA-3′ (SEQ ID NO: 6098)5′-GUGUUCCUUGCAUUUUGGGACAGaa-3′ (SEQ ID NO: 2071)3′-AUCACAAGGAACGUAAAACCCUGUCUU-5′ (SEQ ID NO: 4085) LDHA-1165 Target:5′-TAGTGTTCCTTGCATTTTGGGACAGAA-3′ (SEQ ID NO: 6099)5′-UGUUCCUUGCAUUUUGGGACAGAat-3′ (SEQ ID NO: 2072)3′-UCACAAGGAACGUAAAACCCUGUCUUA-5′ (SEQ ID NO: 4086) LDHA-1166 Target:5′-AGTGTTCCTTGCATTTTGGGACAGAAT-3′ (SEQ ID NO: 6100)5′-GUUCCUUGCAUUUUGGGACAGAAtg-3′ (SEQ ID NO: 2073)3′-CACAAGGAACGUAAAACCCUGUCUUAC-5′ (SEQ ID NO: 4087) LDHA-1167 Target:5′-GTGTTCCTTGCATTTTGGGACAGAATG-3′ (SEQ ID NO: 6101)5′-UUCCUUGCAUUUUGGGACAGAAUgg-3′ (SEQ ID NO: 2074)3′-ACAAGGAACGUAAAACCCUGUCUUACC-5′ (SEQ ID NO: 4088) LDHA-1168 Target:5′-TGTTCCTTGCATTTTGGGACAGAATGG-3′ (SEQ ID NO: 6102)5′-UCCUUGCAUUUUGGGACAGAAUGga-3′ (SEQ ID NO: 2075)3′-CAAGGAACGUAAAACCCUGUCUUACCU-5′ (SEQ ID NO: 4089) LDHA-1169 Target:5′-GTTCCTTGCATTTTGGGACAGAATGGA-3′ (SEQ ID NO: 6103)5′-CCUUGCAUUUUGGGACAGAAUGGaa-3′ (SEQ ID NO: 2076)3′-AAGGAACGUAAAACCCUGUCUUACCUU-5′ (SEQ ID NO: 4090) LDHA-1170 Target:5′-TTCCTTGCATTTTGGGACAGAATGGAA-3′ (SEQ ID NO: 6104)5′-CUUGCAUUUUGGGACAGAAUGGAat-3′ (SEQ ID NO: 2077)3′-AGGAACGUAAAACCCUGUCUUACCUUA-5′ (SEQ ID NO: 4091) LDHA-1171 Target:5′-TCCTTGCATTTTGGGACAGAATGGAAT-3′ (SEQ ID NO: 6105)5′-UUGCAUUUUGGGACAGAAUGGAAtc-3′ (SEQ ID NO: 2078)3′-GGAACGUAAAACCCUGUCUUACCUUAG-5′ (SEQ ID NO: 4092) LDHA-1172 Target:5′-CCTTGCATTTTGGGACAGAATGGAATC-3′ (SEQ ID NO: 6106)5′-UGCAUUUUGGGACAGAAUGGAAUct-3′ (SEQ ID NO: 2079)3′-GAACGUAAAACCCUGUCUUACCUUAGA-5′ (SEQ ID NO: 4093) LDHA-1173 Target:5′-CTTGCATTTTGGGACAGAATGGAATCT-3′ (SEQ ID NO: 6107)5′-GCAUUUUGGGACAGAAUGGAAUCtc-3′ (SEQ ID NO: 2080)3′-AACGUAAAACCCUGUCUUACCUUAGAG-5′ (SEQ ID NO: 4094) LDHA-1174 Target:5′-TTGCATTTTGGGACAGAATGGAATCTC-3′ (SEQ ID NO: 6108)5′-CAUUUUGGGACAGAAUGGAAUCUca-3′ (SEQ ID NO: 2081)3′-ACGUAAAACCCUGUCUUACCUUAGAGU-5′ (SEQ ID NO: 4095) LDHA-1175 Target:5′-TGCATTTTGGGACAGAATGGAATCTCA-3′ (SEQ ID NO: 6109)5′-AUUUUGGGACAGAAUGGAAUCUCag-3′ (SEQ ID NO: 2082)3′-CGUAAAACCCUGUCUUACCUUAGAGUC-5′ (SEQ ID NO: 4096) LDHA-1176 Target:5′-GCATTTTGGGACAGAATGGAATCTCAG-3′ (SEQ ID NO: 6110)5′-UUUUGGGACAGAAUGGAAUCUCAga-3′ (SEQ ID NO: 2083)3′-GUAAAACCCUGUCUUACCUUAGAGUCU-5′ (SEQ ID NO: 4097) LDHA-1177 Target:5′-CATTTTGGGACAGAATGGAATCTCAGA-3′ (SEQ ID NO: 6111)5′-UUUGGGACAGAAUGGAAUCUCAGac-3′ (SEQ ID NO: 2084)3′-UAAAACCCUGUCUUACCUUAGAGUCUG-5′ (SEQ ID NO: 4098) LDHA-1178 Target:5′-ATTTTGGGACAGAATGGAATCTCAGAC-3′ (SEQ ID NO: 6112)5′-UUGGGACAGAAUGGAAUCUCAGAcc-3′ (SEQ ID NO: 2085)3′-AAAACCCUGUCUUACCUUAGAGUCUGG-5′ (SEQ ID NO: 4099) LDHA-1179 Target:5′-TTTTGGGACAGAATGGAATCTCAGACC-3′ (SEQ ID NO: 6113)5′-UGGGACAGAAUGGAAUCUCAGACct-3′ (SEQ ID NO: 2086)3′-AAACCCUGUCUUACCUUAGAGUCUGGA-5′ (SEQ ID NO: 4100) LDHA-1180 Target:5′-TTTGGGACAGAATGGAATCTCAGACCT-3′ (SEQ ID NO: 6114)5′-GGGACAGAAUGGAAUCUCAGACCtt-3′ (SEQ ID NO: 2087)3′-AACCCUGUCUUACCUUAGAGUCUGGAA-5′ (SEQ ID NO: 4101) LDHA-1181 Target:5′-TTGGGACAGAATGGAATCTCAGACCTT-3′ (SEQ ID NO: 6115)5′-GGACAGAAUGGAAUCUCAGACCUtg-3′ (SEQ ID NO: 2088)3′-ACCCUGUCUUACCUUAGAGUCUGGAAC-5′ (SEQ ID NO: 4102) LDHA-1182 Target:5′-TGGGACAGAATGGAATCTCAGACCTTG-3′ (SEQ ID NO: 6116)5′-GACAGAAUGGAAUCUCAGACCUUgt-3′ (SEQ ID NO: 2089)3′-CCCUGUCUUACCUUAGAGUCUGGAACA-5′ (SEQ ID NO: 4103) LDHA-1183 Target:5′-GGGACAGAATGGAATCTCAGACCTTGT-3′ (SEQ ID NO: 6117)5′-ACAGAAUGGAAUCUCAGACCUUGtg-3′ (SEQ ID NO: 2090)3′-CCUGUCUUACCUUAGAGUCUGGAACAC-5′ (SEQ ID NO: 4104) LDHA-1184 Target:5′-GGACAGAATGGAATCTCAGACCTTGTG-3′ (SEQ ID NO: 6118)5′-CAGAAUGGAAUCUCAGACCUUGUga-3′ (SEQ ID NO: 2091)3′-CUGUCUUACCUUAGAGUCUGGAACACU-5′ (SEQ ID NO: 4105) LDHA-1185 Target:5′-GACAGAATGGAATCTCAGACCTTGTGA-3′ (SEQ ID NO: 6119)5′-AGAAUGGAAUCUCAGACCUUGUGaa-3′ (SEQ ID NO: 2092)3′-UGUCUUACCUUAGAGUCUGGAACACUU-5′ (SEQ ID NO: 4106) LDHA-1186 Target:5′-ACAGAATGGAATCTCAGACCTTGTGAA-3′ (SEQ ID NO: 6120)5′-GAAUGGAAUCUCAGACCUUGUGAag-3′ (SEQ ID NO: 2093)3′-GUCUUACCUUAGAGUCUGGAACACUUC-5′ (SEQ ID NO: 4107) LDHA-1187 Target:5′-CAGAATGGAATCTCAGACCTTGTGAAG-3′ (SEQ ID NO: 6121)5′-AAUGGAAUCUCAGACCUUGUGAAgg-3′ (SEQ ID NO: 2094)3′-UCUUACCUUAGAGUCUGGAACACUUCC-5′ (SEQ ID NO: 4108) LDHA-1188 Target:5′-AGAATGGAATCTCAGACCTTGTGAAGG-3′ (SEQ ID NO: 6122)5′-AUGGAAUCUCAGACCUUGUGAAGgt-3′ (SEQ ID NO: 2095)3′-CUUACCUUAGAGUCUGGAACACUUCCA-5′ (SEQ ID NO: 4109) LDHA-1189 Target:5′-GAATGGAATCTCAGACCTTGTGAAGGT-3′ (SEQ ID NO: 6123)5′-UGGAAUCUCAGACCUUGUGAAGGtg-3′ (SEQ ID NO: 2096)3′-UUACCUUAGAGUCUGGAACACUUCCAC-5′ (SEQ ID NO: 4110) LDHA-1190 Target:5′-AATGGAATCTCAGACCTTGTGAAGGTG-3′ (SEQ ID NO: 6124)5′-GGAAUCUCAGACCUUGUGAAGGUga-3′ (SEQ ID NO: 2097)3′-UACCUUAGAGUCUGGAACACUUCCACU-5′ (SEQ ID NO: 4111) LDHA-1191 Target:5′-ATGGAATCTCAGACCTTGTGAAGGTGA-3′ (SEQ ID NO: 6125)5′-GAAUCUCAGACCUUGUGAAGGUGac-3′ (SEQ ID NO: 2098)3′-ACCUUAGAGUCUGGAACACUUCCACUG-5′ (SEQ ID NO: 4112) LDHA-1192 Target:5′-TGGAATCTCAGACCTTGTGAAGGTGAC-3′ (SEQ ID NO: 6126)5′-AAUCUCAGACCUUGUGAAGGUGAct-3′ (SEQ ID NO: 2099)3′-CCUUAGAGUCUGGAACACUUCCACUGA-5′ (SEQ ID NO: 4113) LDHA-1193 Target:5′-GGAATCTCAGACCTTGTGAAGGTGACT-3′ (SEQ ID NO: 6127)5′-AUCUCAGACCUUGUGAAGGUGACtc-3′ (SEQ ID NO: 2100)3′-CUUAGAGUCUGGAACACUUCCACUGAG-5′ (SEQ ID NO: 4114) LDHA-1194 Target:5′-GAATCTCAGACCTTGTGAAGGTGACTC-3′ (SEQ ID NO: 6128)5′-UCUCAGACCUUGUGAAGGUGACUct-3′ (SEQ ID NO: 2101)3′-UUAGAGUCUGGAACACUUCCACUGAGA-5′ (SEQ ID NO: 4115) LDHA-1195 Target:5′-AATCTCAGACCTTGTGAAGGTGACTCT-3′ (SEQ ID NO: 6129)5′-CUCAGACCUUGUGAAGGUGACUCtg-3′ (SEQ ID NO: 2102)3′-UAGAGUCUGGAACACUUCCACUGAGAC-5′ (SEQ ID NO: 4116) LDHA-1196 Target:5′-ATCTCAGACCTTGTGAAGGTGACTCTG-3′ (SEQ ID NO: 6130)5′-UCAGACCUUGUGAAGGUGACUCUga-3′ (SEQ ID NO: 2103)3′-AGAGUCUGGAACACUUCCACUGAGACU-5′ (SEQ ID NO: 4117) LDHA-1197 Target:5′-TCTCAGACCTTGTGAAGGTGACTCTGA-3′ (SEQ ID NO: 6131)5′-CAGACCUUGUGAAGGUGACUCUGac-3′ (SEQ ID NO: 2104)3′-GAGUCUGGAACACUUCCACUGAGACUG-5′ (SEQ ID NO: 4118) LDHA-1198 Target:5′-CTCAGACCTTGTGAAGGTGACTCTGAC-3′ (SEQ ID NO: 6132)5′-AGACCUUGUGAAGGUGACUCUGAct-3′ (SEQ ID NO: 2105)3′-AGUCUGGAACACUUCCACUGAGACUGA-5′ (SEQ ID NO: 4119) LDHA-1199 Target:5′-TCAGACCTTGTGAAGGTGACTCTGACT-3′ (SEQ ID NO: 6133)5′-GACCUUGUGAAGGUGACUCUGACtt-3′ (SEQ ID NO: 2106)3′-GUCUGGAACACUUCCACUGAGACUGAA-5′ (SEQ ID NO: 4120) LDHA-1200 Target:5′-CAGACCTTGTGAAGGTGACTCTGACTT-3′ (SEQ ID NO: 6134)5′-ACCUUGUGAAGGUGACUCUGACUtc-3′ (SEQ ID NO: 2107)3′-UCUGGAACACUUCCACUGAGACUGAAG-5′ (SEQ ID NO: 4121) LDHA-1201 Target:5′-AGACCTTGTGAAGGTGACTCTGACTTC-3′ (SEQ ID NO: 6135)5′-CCUUGUGAAGGUGACUCUGACUUct-3′ (SEQ ID NO: 2108)3′-CUGGAACACUUCCACUGAGACUGAAGA-5′ (SEQ ID NO: 4122) LDHA-1202 Target:5′-GACCTTGTGAAGGTGACTCTGACTTCT-3′ (SEQ ID NO: 6136)5′-CUUGUGAAGGUGACUCUGACUUCtg-3′ (SEQ ID NO: 2109)3′-UGGAACACUUCCACUGAGACUGAAGAC-5′ (SEQ ID NO: 4123) LDHA-1203 Target:5′-ACCTTGTGAAGGTGACTCTGACTTCTG-3′ (SEQ ID NO: 6137)5′-UUGUGAAGGUGACUCUGACUUCUga-3′ (SEQ ID NO: 2110)3′-GGAACACUUCCACUGAGACUGAAGACU-5′ (SEQ ID NO: 4124) LDHA-1204 Target:5′-CCTTGTGAAGGTGACTCTGACTTCTGA-3′ (SEQ ID NO: 6138)5′-UGUGAAGGUGACUCUGACUUCUGag-3′ (SEQ ID NO: 2111)3′-GAACACUUCCACUGAGACUGAAGACUC-5′ (SEQ ID NO: 4125) LDHA-1205 Target:5′-CTTGTGAAGGTGACTCTGACTTCTGAG-3′ (SEQ ID NO: 6139)5′-GUGAAGGUGACUCUGACUUCUGAgg-3′ (SEQ ID NO: 2112)3′-AACACUUCCACUGAGACUGAAGACUCC-5′ (SEQ ID NO: 4126) LDHA-1206 Target:5′-TTGTGAAGGTGACTCTGACTTCTGAGG-3′ (SEQ ID NO: 6140)5′-UGAAGGUGACUCUGACUUCUGAGga-3′ (SEQ ID NO: 2113)3′-ACACUUCCACUGAGACUGAAGACUCCU-5′ (SEQ ID NO: 4127) LDHA-1207 Target:5′-TGTGAAGGTGACTCTGACTTCTGAGGA-3′ (SEQ ID NO: 6141)5′-GAAGGUGACUCUGACUUCUGAGGaa-3′ (SEQ ID NO: 2114)3′-CACUUCCACUGAGACUGAAGACUCCUU-5′ (SEQ ID NO: 4128) LDHA-1208 Target:5′-GTGAAGGTGACTCTGACTTCTGAGGAA-3′ (SEQ ID NO: 6142)5′-AAGGUGACUCUGACUUCUGAGGAag-3′ (SEQ ID NO: 2115)3′-ACUUCCACUGAGACUGAAGACUCCUUC-5′ (SEQ ID NO: 4129) LDHA-1209 Target:5′-TGAAGGTGACTCTGACTTCTGAGGAAG-3′ (SEQ ID NO: 6143)5′-AGGUGACUCUGACUUCUGAGGAAga-3′ (SEQ ID NO: 2116)3′-CUUCCACUGAGACUGAAGACUCCUUCU-5′ (SEQ ID NO: 4130) LDHA-1210 Target:5′-GAAGGTGACTCTGACTTCTGAGGAAGA-3′ (SEQ ID NO: 6144)5′-GGUGACUCUGACUUCUGAGGAAGag-3′ (SEQ ID NO: 2117)3′-UUCCACUGAGACUGAAGACUCCUUCUC-5′ (SEQ ID NO: 4131) LDHA-1211 Target:5′-AAGGTGACTCTGACTTCTGAGGAAGAG-3′ (SEQ ID NO: 6145)5′-GUGACUCUGACUUCUGAGGAAGAgg-3′ (SEQ ID NO: 2118)3′-UCCACUGAGACUGAAGACUCCUUCUCC-5′ (SEQ ID NO: 4132) LDHA-1212 Target:5′-AGGTGACTCTGACTTCTGAGGAAGAGG-3′ (SEQ ID NO: 6146)5′-UGACUCUGACUUCUGAGGAAGAGgc-3′ (SEQ ID NO: 2119)3′-CCACUGAGACUGAAGACUCCUUCUCCG-5′ (SEQ ID NO: 4133) LDHA-1213 Target:5′-GGTGACTCTGACTTCTGAGGAAGAGGC-3′ (SEQ ID NO: 6147)5′-GACUCUGACUUCUGAGGAAGAGGcc-3′ (SEQ ID NO: 2120)3′-CACUGAGACUGAAGACUCCUUCUCCGG-5′ (SEQ ID NO: 4134) LDHA-1214 Target:5′-GTGACTCTGACTTCTGAGGAAGAGGCC-3′ (SEQ ID NO: 6148)5′-ACUCUGACUUCUGAGGAAGAGGCcc-3′ (SEQ ID NO: 2121)3′-ACUGAGACUGAAGACUCCUUCUCCGGG-5′ (SEQ ID NO: 4135) LDHA-1215 Target:5′-TGACTCTGACTTCTGAGGAAGAGGCCC-3′ (SEQ ID NO: 6149)5′-CUCUGACUUCUGAGGAAGAGGCCcg-3′ (SEQ ID NO: 2122)3′-CUGAGACUGAAGACUCCUUCUCCGGGC-5′ (SEQ ID NO: 4136) LDHA-1216 Target:5′-GACTCTGACTTCTGAGGAAGAGGCCCG-3′ (SEQ ID NO: 6150)5′-UCUGACUUCUGAGGAAGAGGCCCgt-3′ (SEQ ID NO: 2123)3′-UGAGACUGAAGACUCCUUCUCCGGGCA-5′ (SEQ ID NO: 4137) LDHA-1217 Target:5′-ACTCTGACTTCTGAGGAAGAGGCCCGT-3′ (SEQ ID NO: 6151)5′-CUGACUUCUGAGGAAGAGGCCCGtt-3′ (SEQ ID NO: 2124)3′-GAGACUGAAGACUCCUUCUCCGGGCAA-5′ (SEQ ID NO: 4138) LDHA-1218 Target:5′-CTCTGACTTCTGAGGAAGAGGCCCGTT-3′ (SEQ ID NO: 6152)5′-UGACUUCUGAGGAAGAGGCCCGUtt-3′ (SEQ ID NO: 2125)3′-AGACUGAAGACUCCUUCUCCGGGCAAA-5′ (SEQ ID NO: 4139) LDHA-1219 Target:5′-TCTGACTTCTGAGGAAGAGGCCCGTTT-3′ (SEQ ID NO: 6153)5′-GACUUCUGAGGAAGAGGCCCGUUtg-3′ (SEQ ID NO: 2126)3′-GACUGAAGACUCCUUCUCCGGGCAAAC-5′ (SEQ ID NO: 4140) LDHA-1220 Target:5′-CTGACTTCTGAGGAAGAGGCCCGTTTG-3′ (SEQ ID NO: 6154)5′-ACUUCUGAGGAAGAGGCCCGUUUga-3′ (SEQ ID NO: 2127)3′-ACUGAAGACUCCUUCUCCGGGCAAACU-5′ (SEQ ID NO: 4141) LDHA-1221 Target:5′-TGACTTCTGAGGAAGAGGCCCGTTTGA-3′ (SEQ ID NO: 6155)5′-CUUCUGAGGAAGAGGCCCGUUUGaa-3′ (SEQ ID NO: 2128)3′-CUGAAGACUCCUUCUCCGGGCAAACUU-5′ (SEQ ID NO: 4142) LDHA-1222 Target:5′-GACTTCTGAGGAAGAGGCCCGTTTGAA-3′ (SEQ ID NO: 6156)5′-UUCUGAGGAAGAGGCCCGUUUGAag-3′ (SEQ ID NO: 2129)3′-UGAAGACUCCUUCUCCGGGCAAACUUC-5′ (SEQ ID NO: 4143) LDHA-1223 Target:5′-ACTTCTGAGGAAGAGGCCCGTTTGAAG-3′ (SEQ ID NO: 6157)5′-UCUGAGGAAGAGGCCCGUUUGAAga-3′ (SEQ ID NO: 2130)3′-GAAGACUCCUUCUCCGGGCAAACUUCU-5′ (SEQ ID NO: 4144) LDHA-1224 Target:5′-CTTCTGAGGAAGAGGCCCGTTTGAAGA-3′ (SEQ ID NO: 6158)5′-CUGAGGAAGAGGCCCGUUUGAAGaa-3′ (SEQ ID NO: 2131)3′-AAGACUCCUUCUCCGGGCAAACUUCUU-5′ (SEQ ID NO: 4145) LDHA-1225 Target:5′-TTCTGAGGAAGAGGCCCGTTTGAAGAA-3′ (SEQ ID NO: 6159)5′-UGAGGAAGAGGCCCGUUUGAAGAag-3′ (SEQ ID NO: 2132)3′-AGACUCCUUCUCCGGGCAAACUUCUUC-5′ (SEQ ID NO: 4146) LDHA-1226 Target:5′-TCTGAGGAAGAGGCCCGTTTGAAGAAG-3′ (SEQ ID NO: 6160)5′-GAGGAAGAGGCCCGUUUGAAGAAga-3′ (SEQ ID NO: 2133)3′-GACUCCUUCUCCGGGCAAACUUCUUCU-5′ (SEQ ID NO: 4147) LDHA-1227 Target:5′-CTGAGGAAGAGGCCCGTTTGAAGAAGA-3′ (SEQ ID NO: 6161)5′-AGGAAGAGGCCCGUUUGAAGAAGag-3′ (SEQ ID NO: 2134)3′-ACUCCUUCUCCGGGCAAACUUCUUCUC-5′ (SEQ ID NO: 4148) LDHA-1228 Target:5′-TGAGGAAGAGGCCCGTTTGAAGAAGAG-3′ (SEQ ID NO: 6162)5′-GGAAGAGGCCCGUUUGAAGAAGAgt-3′ (SEQ ID NO: 2135)3′-CUCCUUCUCCGGGCAAACUUCUUCUCA-5′ (SEQ ID NO: 4149) LDHA-1229 Target:5′-GAGGAAGAGGCCCGTTTGAAGAAGAGT-3′ (SEQ ID NO: 6163)5′-GAAGAGGCCCGUUUGAAGAAGAGtg-3′ (SEQ ID NO: 2136)3′-UCCUUCUCCGGGCAAACUUCUUCUCAC-5′ (SEQ ID NO: 4150) LDHA-1230 Target:5′-AGGAAGAGGCCCGTTTGAAGAAGAGTG-3′ (SEQ ID NO: 6164)5′-AAGAGGCCCGUUUGAAGAAGAGUgc-3′ (SEQ ID NO: 2137)3′-CCUUCUCCGGGCAAACUUCUUCUCACG-5′ (SEQ ID NO: 4151) LDHA-1231 Target:5′-GGAAGAGGCCCGTTTGAAGAAGAGTGC-3′ (SEQ ID NO: 6165)5′-AGAGGCCCGUUUGAAGAAGAGUGca-3′ (SEQ ID NO: 2138)3′-CUUCUCCGGGCAAACUUCUUCUCACGU-5′ (SEQ ID NO: 4152) LDHA-1232 Target:5′-GAAGAGGCCCGTTTGAAGAAGAGTGCA-3′ (SEQ ID NO: 6166)5′-GAGGCCCGUUUGAAGAAGAGUGCag-3′ (SEQ ID NO: 2139)3′-UUCUCCGGGCAAACUUCUUCUCACGUC-5′ (SEQ ID NO: 4153) LDHA-1233 Target:5′-AAGAGGCCCGTTTGAAGAAGAGTGCAG-3′ (SEQ ID NO: 6167)5′-AGGCCCGUUUGAAGAAGAGUGCAga-3′ (SEQ ID NO: 2140)3′-UCUCCGGGCAAACUUCUUCUCACGUCU-5′ (SEQ ID NO: 4154) LDHA-1234 Target:5′-AGAGGCCCGTTTGAAGAAGAGTGCAGA-3′ (SEQ ID NO: 6168)5′-GGCCCGUUUGAAGAAGAGUGCAGat-3′ (SEQ ID NO: 2141)3′-CUCCGGGCAAACUUCUUCUCACGUCUA-5′ (SEQ ID NO: 4155) LDHA-1235 Target:5′-GAGGCCCGTTTGAAGAAGAGTGCAGAT-3′ (SEQ ID NO: 6169)5′-GCCCGUUUGAAGAAGAGUGCAGAta-3′ (SEQ ID NO: 2142)3′-UCCGGGCAAACUUCUUCUCACGUCUAU-5′ (SEQ ID NO: 4156) LDHA-1236 Target:5′-AGGCCCGTTTGAAGAAGAGTGCAGATA-3′ (SEQ ID NO: 6170)5′-CCCGUUUGAAGAAGAGUGCAGAUac-3′ (SEQ ID NO: 2143)3′-CCGGGCAAACUUCUUCUCACGUCUAUG-5′ (SEQ ID NO: 4157) LDHA-1237 Target:5′-GGCCCGTTTGAAGAAGAGTGCAGATAC-3′ (SEQ ID NO: 6171)5′-CCGUUUGAAGAAGAGUGCAGAUAca-3′ (SEQ ID NO: 2144)3′-CGGGCAAACUUCUUCUCACGUCUAUGU-5′ (SEQ ID NO: 4158) LDHA-1238 Target:5′-GCCCGTTTGAAGAAGAGTGCAGATACA-3′ (SEQ ID NO: 6172)5′-CGUUUGAAGAAGAGUGCAGAUACac-3′ (SEQ ID NO: 2145)3′-GGGCAAACUUCUUCUCACGUCUAUGUG-5′ (SEQ ID NO: 4159) LDHA-1239 Target:5′-CCCGTTTGAAGAAGAGTGCAGATACAC-3′ (SEQ ID NO: 6173)5′-GUUUGAAGAAGAGUGCAGAUACAct-3′ (SEQ ID NO: 2146)3′-GGCAAACUUCUUCUCACGUCUAUGUGA-5′ (SEQ ID NO: 4160) LDHA-1240 Target:5′-CCGTTTGAAGAAGAGTGCAGATACACT-3′ (SEQ ID NO: 6174)5′-UUUGAAGAAGAGUGCAGAUACACtt-3′ (SEQ ID NO: 2147)3′-GCAAACUUCUUCUCACGUCUAUGUGAA-5′ (SEQ ID NO: 4161) LDHA-1241 Target:5′-CGTTTGAAGAAGAGTGCAGATACACTT-3′ (SEQ ID NO: 6175)5′-UUGAAGAAGAGUGCAGAUACACUtt-3′ (SEQ ID NO: 2148)3′-CAAACUUCUUCUCACGUCUAUGUGAAA-5′ (SEQ ID NO: 4162) LDHA-1242 Target:5′-GTTTGAAGAAGAGTGCAGATACACTTT-3′ (SEQ ID NO: 6176)5′-UGAAGAAGAGUGCAGAUACACUUtg-3′ (SEQ ID NO: 2149)3′-AAACUUCUUCUCACGUCUAUGUGAAAC-5′ (SEQ ID NO: 4163) LDHA-1243 Target:5′-TTTGAAGAAGAGTGCAGATACACTTTG-3′ (SEQ ID NO: 6177)5′-GAAGAAGAGUGCAGAUACACUUUgg-3′ (SEQ ID NO: 2150)3′-AACUUCUUCUCACGUCUAUGUGAAACC-5′ (SEQ ID NO: 4164) LDHA-1244 Target:5′-TTGAAGAAGAGTGCAGATACACTTTGG-3′ (SEQ ID NO: 6178)5′-AAGAAGAGUGCAGAUACACUUUGgg-3′ (SEQ ID NO: 2151)3′-ACUUCUUCUCACGUCUAUGUGAAACCC-5′ (SEQ ID NO: 4165) LDHA-1245 Target:5′-TGAAGAAGAGTGCAGATACACTTTGGG-3′ (SEQ ID NO: 6179)5′-AGAAGAGUGCAGAUACACUUUGGgg-3′ (SEQ ID NO: 2152)3′-CUUCUUCUCACGUCUAUGUGAAACCCC-5′ (SEQ ID NO: 4166) LDHA-1246 Target:5′-GAAGAAGAGTGCAGATACACTTTGGGG-3′ (SEQ ID NO: 6180)5′-GAAGAGUGCAGAUACACUUUGGGgg-3′ (SEQ ID NO: 2153)3′-UUCUUCUCACGUCUAUGUGAAACCCCC-5′ (SEQ ID NO: 4167) LDHA-1247 Target:5′-AAGAAGAGTGCAGATACACTTTGGGGG-3′ (SEQ ID NO: 6181)5′-AAGAGUGCAGAUACACUUUGGGGga-3′ (SEQ ID NO: 2154)3′-UCUUCUCACGUCUAUGUGAAACCCCCU-5′ (SEQ ID NO: 4168) LDHA-1248 Target:5′-AGAAGAGTGCAGATACACTTTGGGGGA-3′ (SEQ ID NO: 6182)5′-AGAGUGCAGAUACACUUUGGGGGat-3′ (SEQ ID NO: 2155)3′-CUUCUCACGUCUAUGUGAAACCCCCUA-5′ (SEQ ID NO: 4169) LDHA-1249 Target:5′-GAAGAGTGCAGATACACTTTGGGGGAT-3′ (SEQ ID NO: 6183)5′-GAGUGCAGAUACACUUUGGGGGAtc-3′ (SEQ ID NO: 2156)3′-UUCUCACGUCUAUGUGAAACCCCCUAG-5′ (SEQ ID NO: 4170) LDHA-1250 Target:5′-AAGAGTGCAGATACACTTTGGGGGATC-3′ (SEQ ID NO: 6184)5′-AGUGCAGAUACACUUUGGGGGAUcc-3′ (SEQ ID NO: 2157)3′-UCUCACGUCUAUGUGAAACCCCCUAGG-5′ (SEQ ID NO: 4171) LDHA-1251 Target:5′-AGAGTGCAGATACACTTTGGGGGATCC-3′ (SEQ ID NO: 6185)5′-GUGCAGAUACACUUUGGGGGAUCca-3′ (SEQ ID NO: 2158)3′-CUCACGUCUAUGUGAAACCCCCUAGGU-5′ (SEQ ID NO: 4172) LDHA-1252 Target:5′-GAGTGCAGATACACTTTGGGGGATCCA-3′ (SEQ ID NO: 6186)5′-UGCAGAUACACUUUGGGGGAUCCaa-3′ (SEQ ID NO: 2159)3′-UCACGUCUAUGUGAAACCCCCUAGGUU-5′ (SEQ ID NO: 4173) LDHA-1253 Target:5′-AGTGCAGATACACTTTGGGGGATCCAA-3′ (SEQ ID NO: 6187)5′-GCAGAUACACUUUGGGGGAUCCAaa-3′ (SEQ ID NO: 2160)3′-CACGUCUAUGUGAAACCCCCUAGGUUU-5′ (SEQ ID NO: 4174) LDHA-1254 Target:5′-GTGCAGATACACTTTGGGGGATCCAAA-3′ (SEQ ID NO: 6188)5′-CAGAUACACUUUGGGGGAUCCAAaa-3′ (SEQ ID NO: 2161)3′-ACGUCUAUGUGAAACCCCCUAGGUUUU-5′ (SEQ ID NO: 4175) LDHA-1255 Target:5′-TGCAGATACACTTTGGGGGATCCAAAA-3′ (SEQ ID NO: 6189)5′-AGAUACACUUUGGGGGAUCCAAAag-3′ (SEQ ID NO: 2162)3′-CGUCUAUGUGAAACCCCCUAGGUUUUC-5′ (SEQ ID NO: 4176) LDHA-1256 Target:5′-GCAGATACACTTTGGGGGATCCAAAAG-3′ (SEQ ID NO: 6190)5′-GAUACACUUUGGGGGAUCCAAAAgg-3′ (SEQ ID NO: 2163)3′-GUCUAUGUGAAACCCCCUAGGUUUUCC-5′ (SEQ ID NO: 4177) LDHA-1257 Target:5′-CAGATACACTTTGGGGGATCCAAAAGG-3′ (SEQ ID NO: 6191)5′-AUACACUUUGGGGGAUCCAAAAGga-3′ (SEQ ID NO: 2164)3′-UCUAUGUGAAACCCCCUAGGUUUUCCU-5′ (SEQ ID NO: 4178) LDHA-1258 Target:5′-AGATACACTTTGGGGGATCCAAAAGGA-3′ (SEQ ID NO: 6192)5′-UACACUUUGGGGGAUCCAAAAGGag-3′ (SEQ ID NO: 2165)3′-CUAUGUGAAACCCCCUAGGUUUUCCUC-5′ (SEQ ID NO: 4179) LDHA-1259 Target:5′-GATACACTTTGGGGGATCCAAAAGGAG-3′ (SEQ ID NO: 6193)5′-ACACUUUGGGGGAUCCAAAAGGAgc-3′ (SEQ ID NO: 2166)3′-UAUGUGAAACCCCCUAGGUUUUCCUCG-5′ (SEQ ID NO: 4180) LDHA-1260 Target:5′-ATACACTTTGGGGGATCCAAAAGGAGC-3′ (SEQ ID NO: 6194)5′-CACUUUGGGGGAUCCAAAAGGAGct-3′ (SEQ ID NO: 2167)3′-AUGUGAAACCCCCUAGGUUUUCCUCGA-5′ (SEQ ID NO: 4181) LDHA-1261 Target:5′-TACACTTTGGGGGATCCAAAAGGAGCT-3′ (SEQ ID NO: 6195)5′-ACUUUGGGGGAUCCAAAAGGAGCtg-3′ (SEQ ID NO: 2168)3′-UGUGAAACCCCCUAGGUUUUCCUCGAC-5′ (SEQ ID NO: 4182) LDHA-1262 Target:5′-ACACTTTGGGGGATCCAAAAGGAGCTG-3′ (SEQ ID NO: 6196)5′-CUUUGGGGGAUCCAAAAGGAGCUgc-3′ (SEQ ID NO: 2169)3′-GUGAAACCCCCUAGGUUUUCCUCGACG-5′ (SEQ ID NO: 4183) LDHA-1263 Target:5′-CACTTTGGGGGATCCAAAAGGAGCTGC-3′ (SEQ ID NO: 6197)5′-UUUGGGGGAUCCAAAAGGAGCUGca-3′ (SEQ ID NO: 2170)3′-UGAAACCCCCUAGGUUUUCCUCGACGU-5′ (SEQ ID NO: 4184) LDHA-1264 Target:5′-ACTTTGGGGGATCCAAAAGGAGCTGCA-3′ (SEQ ID NO: 6198)5′-UUGGGGGAUCCAAAAGGAGCUGCaa-3′ (SEQ ID NO: 2171)3′-GAAACCCCCUAGGUUUUCCUCGACGUU-5′ (SEQ ID NO: 4185) LDHA-1265 Target:5′-CTTTGGGGGATCCAAAAGGAGCTGCAA-3′ (SEQ ID NO: 6199)5′-UGGGGGAUCCAAAAGGAGCUGCAat-3′ (SEQ ID NO: 2172)3′-AAACCCCCUAGGUUUUCCUCGACGUUA-5′ (SEQ ID NO: 4186) LDHA-1266 Target:5′-TTTGGGGGATCCAAAAGGAGCTGCAAT-3′ (SEQ ID NO: 6200)5′-GGGGGAUCCAAAAGGAGCUGCAAtt-3′ (SEQ ID NO: 2173)3′-AACCCCCUAGGUUUUCCUCGACGUUAA-5′ (SEQ ID NO: 4187) LDHA-1267 Target:5′-TTGGGGGATCCAAAAGGAGCTGCAATT-3′ (SEQ ID NO: 6201)5′-GGGGAUCCAAAAGGAGCUGCAAUtt-3′ (SEQ ID NO: 2174)3′-ACCCCCUAGGUUUUCCUCGACGUUAAA-5′ (SEQ ID NO: 4188) LDHA-1268 Target:5′-TGGGGGATCCAAAAGGAGCTGCAATTT-3′ (SEQ ID NO: 6202)5′-GGGAUCCAAAAGGAGCUGCAAUUtt-3′ (SEQ ID NO: 2175)3′-CCCCCUAGGUUUUCCUCGACGUUAAAA-5′ (SEQ ID NO: 4189) LDHA-1269 Target:5′-GGGGGATCCAAAAGGAGCTGCAATTTT-3′ (SEQ ID NO: 6203)5′-GGAUCCAAAAGGAGCUGCAAUUUta-3′ (SEQ ID NO: 2176)3′-CCCCUAGGUUUUCCUCGACGUUAAAAU-5′ (SEQ ID NO: 4190) LDHA-1270 Target:5′-GGGGATCCAAAAGGAGCTGCAATTTTA-3′ (SEQ ID NO: 6204)5′-GAUCCAAAAGGAGCUGCAAUUUUaa-3′ (SEQ ID NO: 2177)3′-CCCUAGGUUUUCCUCGACGUUAAAAUU-5′ (SEQ ID NO: 4191) LDHA-1271 Target:5′-GGGATCCAAAAGGAGCTGCAATTTTAA-3′ (SEQ ID NO: 6205)5′-AUCCAAAAGGAGCUGCAAUUUUAaa-3′ (SEQ ID NO: 2178)3′-CCUAGGUUUUCCUCGACGUUAAAAUUU-5′ (SEQ ID NO: 4192) LDHA-1272 Target:5′-GGATCCAAAAGGAGCTGCAATTTTAAA-3′ (SEQ ID NO: 6206)5′-UCCAAAAGGAGCUGCAAUUUUAAag-3′ (SEQ ID NO: 2179)3′-CUAGGUUUUCCUCGACGUUAAAAUUUC-5′ (SEQ ID NO: 4193) LDHA-1273 Target:5′-GATCCAAAAGGAGCTGCAATTTTAAAG-3′ (SEQ ID NO: 6207)5′-CCAAAAGGAGCUGCAAUUUUAAAgt-3′ (SEQ ID NO: 2180)3′-UAGGUUUUCCUCGACGUUAAAAUUUCA-5′ (SEQ ID NO: 4194) LDHA-1274 Target:5′-ATCCAAAAGGAGCTGCAATTTTAAAGT-3′ (SEQ ID NO: 6208)5′-CAAAAGGAGCUGCAAUUUUAAAGtc-3′ (SEQ ID NO: 2181)3′-AGGUUUUCCUCGACGUUAAAAUUUCAG-5′ (SEQ ID NO: 4195) LDHA-1275 Target:5′-TCCAAAAGGAGCTGCAATTTTAAAGTC-3′ (SEQ ID NO: 6209)5′-AAAAGGAGCUGCAAUUUUAAAGUct-3′ (SEQ ID NO: 2182)3′-GGUUUUCCUCGACGUUAAAAUUUCAGA-5′ (SEQ ID NO: 4196) LDHA-1276 Target:5′-CCAAAAGGAGCTGCAATTTTAAAGTCT-3′ (SEQ ID NO: 6210)5′-AAAGGAGCUGCAAUUUUAAAGUCtt-3′ (SEQ ID NO: 2183)3′-GUUUUCCUCGACGUUAAAAUUUCAGAA-5′ (SEQ ID NO: 4197) LDHA-1277 Target:5′-CAAAAGGAGCTGCAATTTTAAAGTCTT-3′ (SEQ ID NO: 6211)5′-AAGGAGCUGCAAUUUUAAAGUCUtc-3′ (SEQ ID NO: 2184)3′-UUUUCCUCGACGUUAAAAUUUCAGAAG-5′ (SEQ ID NO: 4198) LDHA-1278 Target:5′-AAAAGGAGCTGCAATTTTAAAGTCTTC-3′ (SEQ ID NO: 6212)5′-AGGAGCUGCAAUUUUAAAGUCUUct-3′ (SEQ ID NO: 2185)3′-UUUCCUCGACGUUAAAAUUUCAGAAGA-5′ (SEQ ID NO: 4199) LDHA-1279 Target:5′-AAAGGAGCTGCAATTTTAAAGTCTTCT-3′ (SEQ ID NO: 6213)5′-GGAGCUGCAAUUUUAAAGUCUUCtg-3′ (SEQ ID NO: 2186)3′-UUCCUCGACGUUAAAAUUUCAGAAGAC-5′ (SEQ ID NO: 4200) LDHA-1280 Target:5′-AAGGAGCTGCAATTTTAAAGTCTTCTG-3′ (SEQ ID NO: 6214)5′-GAGCUGCAAUUUUAAAGUCUUCUga-3′ (SEQ ID NO: 2187)3′-UCCUCGACGUUAAAAUUUCAGAAGACU-5′ (SEQ ID NO: 4201) LDHA-1281 Target:5′-AGGAGCTGCAATTTTAAAGTCTTCTGA-3′ (SEQ ID NO: 6215)5′-AGCUGCAAUUUUAAAGUCUUCUGat-3′ (SEQ ID NO: 2188)3′-CCUCGACGUUAAAAUUUCAGAAGACUA-5′ (SEQ ID NO: 4202) LDHA-1282 Target:5′-GGAGCTGCAATTTTAAAGTCTTCTGAT-3′ (SEQ ID NO: 6216)5′-GCUGCAAUUUUAAAGUCUUCUGAtg-3′ (SEQ ID NO: 2189)3′-CUCGACGUUAAAAUUUCAGAAGACUAC-5′ (SEQ ID NO: 4203) LDHA-1283 Target:5′-GAGCTGCAATTTTAAAGTCTTCTGATG-3′ (SEQ ID NO: 6217)5′-CUGCAAUUUUAAAGUCUUCUGAUgt-3′ (SEQ ID NO: 2190)3′-UCGACGUUAAAAUUUCAGAAGACUACA-5′ (SEQ ID NO: 4204) LDHA-1284 Target:5′-AGCTGCAATTTTAAAGTCTTCTGATGT-3′ (SEQ ID NO: 6218)5′-UGCAAUUUUAAAGUCUUCUGAUGtc-3′ (SEQ ID NO: 2191)3′-CGACGUUAAAAUUUCAGAAGACUACAG-5′ (SEQ ID NO: 4205) LDHA-1285 Target:5′-GCTGCAATTTTAAAGTCTTCTGATGTC-3′ (SEQ ID NO: 6219)5′-AAUUUUAAAGUCUUCUGAUGUCAta-3′ (SEQ ID NO: 2192)3′-CGUUAAAAUUUCAGAAGACUACAGUAU-5′ (SEQ ID NO: 4206) LDHA-1288 Target:5′-GCAATTTTAAAGTCTTCTGATGTCATA-3′ (SEQ ID NO: 6220)5′-AUUUUAAAGUCUUCUGAUGUCAUat-3′ (SEQ ID NO: 2193)3′-GUUAAAAUUUCAGAAGACUACAGUAUA-5′ (SEQ ID NO: 4207) LDHA-1289 Target:5′-CAATTTTAAAGTCTTCTGATGTCATAT-3′ (SEQ ID NO: 6221)5′-UUUUAAAGUCUUCUGAUGUCAUAtc-3′ (SEQ ID NO: 2194)3′-UUAAAAUUUCAGAAGACUACAGUAUAG-5′ (SEQ ID NO: 4208) LDHA-1290 Target:5′-AATTTTAAAGTCTTCTGATGTCATATC-3′ (SEQ ID NO: 6222)5′-UUUAAAGUCUUCUGAUGUCAUAUca-3′ (SEQ ID NO: 2195)3′-UAAAAUUUCAGAAGACUACAGUAUAGU-5′ (SEQ ID NO: 4209) LDHA-1291 Target:5′-ATTTTAAAGTCTTCTGATGTCATATCA-3′ (SEQ ID NO: 6223)5′-AAGUCUUCUGAUGUCAUAUCAUUtc-3′ (SEQ ID NO: 2196)3′-AUUUCAGAAGACUACAGUAUAGUAAAG-5′ (SEQ ID NO: 4210) LDHA-1295 Target:5′-TAAAGTCTTCTGATGTCATATCATTTC-3′ (SEQ ID NO: 6224)5′-AGUCUUCUGAUGUCAUAUCAUUUca-3′ (SEQ ID NO: 2197)3′-UUUCAGAAGACUACAGUAUAGUAAAGU-5′ (SEQ ID NO: 4211) LDHA-1296 Target:5′-AAAGTCTTCTGATGTCATATCATTTCA-3′ (SEQ ID NO: 6225)5′-GUCUUCUGAUGUCAUAUCAUUUCac-3′ (SEQ ID NO: 2198)3′-UUCAGAAGACUACAGUAUAGUAAAGUG-5′ (SEQ ID NO: 4212) LDHA-1297 Target:5′-AAGTCTTCTGATGTCATATCATTTCAC-3′ (SEQ ID NO: 6226)5′-UCUUCUGAUGUCAUAUCAUUUCAct-3′ (SEQ ID NO: 2199)3′-UCAGAAGACUACAGUAUAGUAAAGUGA-5′ (SEQ ID NO: 4213) LDHA-1298 Target:5′-AGTCTTCTGATGTCATATCATTTCACT-3′ (SEQ ID NO: 6227)5′-CUUCUGAUGUCAUAUCAUUUCACtg-3′ (SEQ ID NO: 2200)3′-CAGAAGACUACAGUAUAGUAAAGUGAC-5′ (SEQ ID NO: 4214) LDHA-1299 Target:5′-GTCTTCTGATGTCATATCATTTCACTG-3′ (SEQ ID NO: 6228)5′-UUCUGAUGUCAUAUCAUUUCACUgt-3′ (SEQ ID NO: 2201)3′-AGAAGACUACAGUAUAGUAAAGUGACA-5′ (SEQ ID NO: 4215) LDHA-1300 Target:5′-TCTTCTGATGTCATATCATTTCACTGT-3′ (SEQ ID NO: 6229)5′-UCUGAUGUCAUAUCAUUUCACUGtc-3′ (SEQ ID NO: 2202)3′-GAAGACUACAGUAUAGUAAAGUGACAG-5′ (SEQ ID NO: 4216) LDHA-1301 Target:5′-CTTCTGATGTCATATCATTTCACTGTC-3′ (SEQ ID NO: 6230)5′-CUGAUGUCAUAUCAUUUCACUGUct-3′ (SEQ ID NO: 2203)3′-AAGACUACAGUAUAGUAAAGUGACAGA-5′ (SEQ ID NO: 4217) LDHA-1302 Target:5′-TTCTGATGTCATATCATTTCACTGTCT-3′ (SEQ ID NO: 6231)5′-UGAUGUCAUAUCAUUUCACUGUCta-3′ (SEQ ID NO: 2204)3′-AGACUACAGUAUAGUAAAGUGACAGAU-5′ (SEQ ID NO: 4218) LDHA-1303 Target:5′-TCTGATGTCATATCATTTCACTGTCTA-3′ (SEQ ID NO: 6232)5′-GAUGUCAUAUCAUUUCACUGUCUag-3′ (SEQ ID NO: 2205)3′-GACUACAGUAUAGUAAAGUGACAGAUC-5′ (SEQ ID NO: 4219) LDHA-1304 Target:5′-CTGATGTCATATCATTTCACTGTCTAG-3′ (SEQ ID NO: 6233)5′-AUGUCAUAUCAUUUCACUGUCUAgg-3′ (SEQ ID NO: 2206)3′-ACUACAGUAUAGUAAAGUGACAGAUCC-5′ (SEQ ID NO: 4220) LDHA-1305 Target:5′-TGATGTCATATCATTTCACTGTCTAGG-3′ (SEQ ID NO: 6234)5′-UGUCAUAUCAUUUCACUGUCUAGgc-3′ (SEQ ID NO: 2207)3′-CUACAGUAUAGUAAAGUGACAGAUCCG-5′ (SEQ ID NO: 4221) LDHA-1306 Target:5′-GATGTCATATCATTTCACTGTCTAGGC-3′ (SEQ ID NO: 6235)5′-GUCAUAUCAUUUCACUGUCUAGGct-3′ (SEQ ID NO: 2208)3′-UACAGUAUAGUAAAGUGACAGAUCCGA-5′ (SEQ ID NO: 4222) LDHA-1307 Target:5′-ATGTCATATCATTTCACTGTCTAGGCT-3′ (SEQ ID NO: 6236)5′-UCAUAUCAUUUCACUGUCUAGGCta-3′ (SEQ ID NO: 2209)3′-ACAGUAUAGUAAAGUGACAGAUCCGAU-5′ (SEQ ID NO: 4223) LDHA-1308 Target:5′-TGTCATATCATTTCACTGTCTAGGCTA-3′ (SEQ ID NO: 6237)5′-CAUAUCAUUUCACUGUCUAGGCUac-3′ (SEQ ID NO: 2210)3′-CAGUAUAGUAAAGUGACAGAUCCGAUG-5′ (SEQ ID NO: 4224) LDHA-1309 Target:5′-GTCATATCATTTCACTGTCTAGGCTAC-3′ (SEQ ID NO: 6238)5′-AUAUCAUUUCACUGUCUAGGCUAca-3′ (SEQ ID NO: 2211)3′-AGUAUAGUAAAGUGACAGAUCCGAUGU-5′ (SEQ ID NO: 4225) LDHA-1310 Target:5′-TCATATCATTTCACTGTCTAGGCTACA-3′ (SEQ ID NO: 6239)5′-UAUCAUUUCACUGUCUAGGCUACaa-3′ (SEQ ID NO: 2212)3′-GUAUAGUAAAGUGACAGAUCCGAUGUU-5′ (SEQ ID NO: 4226) LDHA-1311 Target:5′-CATATCATTTCACTGTCTAGGCTACAA-3′ (SEQ ID NO: 6240)5′-AUCAUUUCACUGUCUAGGCUACAac-3′ (SEQ ID NO: 2213)3′-UAUAGUAAAGUGACAGAUCCGAUGUUG-5′ (SEQ ID NO: 4227) LDHA-1312 Target:5′-ATATCATTTCACTGTCTAGGCTACAAC-3′ (SEQ ID NO: 6241)5′-UCAUUUCACUGUCUAGGCUACAAca-3′ (SEQ ID NO: 2214)3′-AUAGUAAAGUGACAGAUCCGAUGUUGU-5′ (SEQ ID NO: 4228) LDHA-1313 Target:5′-TATCATTTCACTGTCTAGGCTACAACA-3′ (SEQ ID NO: 6242)5′-CAUUUCACUGUCUAGGCUACAACag-3′ (SEQ ID NO: 2215)3′-UAGUAAAGUGACAGAUCCGAUGUUGUC-5′ (SEQ ID NO: 4229) LDHA-1314 Target:5′-ATCATTTCACTGTCTAGGCTACAACAG-3′ (SEQ ID NO: 6243)5′-AUUUCACUGUCUAGGCUACAACAgg-3′ (SEQ ID NO: 2216)3′-AGUAAAGUGACAGAUCCGAUGUUGUCC-5′ (SEQ ID NO: 4230) LDHA-1315 Target:5′-TCATTTCACTGTCTAGGCTACAACAGG-3′ (SEQ ID NO: 6244)5′-UUUCACUGUCUAGGCUACAACAGga-3′ (SEQ ID NO: 2217)3′-GUAAAGUGACAGAUCCGAUGUUGUCCU-5′ (SEQ ID NO: 4231) LDHA-1316 Target:5′-CATTTCACTGTCTAGGCTACAACAGGA-3′ (SEQ ID NO: 6245)5′-UUCACUGUCUAGGCUACAACAGGat-3′ (SEQ ID NO: 2218)3′-UAAAGUGACAGAUCCGAUGUUGUCCUA-5′ (SEQ ID NO: 4232) LDHA-1317 Target:5′-ATTTCACTGTCTAGGCTACAACAGGAT-3′ (SEQ ID NO: 6246)5′-UCACUGUCUAGGCUACAACAGGAtt-3′ (SEQ ID NO: 2219)3′-AAAGUGACAGAUCCGAUGUUGUCCUAA-5′ (SEQ ID NO: 4233) LDHA-1318 Target:5′-TTTCACTGTCTAGGCTACAACAGGATT-3′ (SEQ ID NO: 6247)5′-CACUGUCUAGGCUACAACAGGAUtc-3′ (SEQ ID NO: 2220)3′-AAGUGACAGAUCCGAUGUUGUCCUAAG-5′ (SEQ ID NO: 4234) LDHA-1319 Target:5′-TTCACTGTCTAGGCTACAACAGGATTC-3′ (SEQ ID NO: 6248)5′-ACUGUCUAGGCUACAACAGGAUUct-3′ (SEQ ID NO: 2221)3′-AGUGACAGAUCCGAUGUUGUCCUAAGA-5′ (SEQ ID NO: 4235) LDHA-1320 Target:5′-TCACTGTCTAGGCTACAACAGGATTCT-3′ (SEQ ID NO: 6249)5′-CUGUCUAGGCUACAACAGGAUUCta-3′ (SEQ ID NO: 2222)3′-GUGACAGAUCCGAUGUUGUCCUAAGAU-5′ (SEQ ID NO: 4236) LDHA-1321 Target:5′-CACTGTCTAGGCTACAACAGGATTCTA-3′ (SEQ ID NO: 6250)5′-UGUCUAGGCUACAACAGGAUUCUag-3′ (SEQ ID NO: 2223)3′-UGACAGAUCCGAUGUUGUCCUAAGAUC-5′ (SEQ ID NO: 4237) LDHA-1322 Target:5′-ACTGTCTAGGCTACAACAGGATTCTAG-3′ (SEQ ID NO: 6251)5′-GUCUAGGCUACAACAGGAUUCUAgg-3′ (SEQ ID NO: 2224)3′-GACAGAUCCGAUGUUGUCCUAAGAUCC-5′ (SEQ ID NO: 4238) LDHA-1323 Target:5′-CTGTCTAGGCTACAACAGGATTCTAGG-3′ (SEQ ID NO: 6252)5′-UCUAGGCUACAACAGGAUUCUAGgt-3′ (SEQ ID NO: 2225)3′-ACAGAUCCGAUGUUGUCCUAAGAUCCA-5′ (SEQ ID NO: 4239) LDHA-1324 Target:5′-TGTCTAGGCTACAACAGGATTCTAGGT-3′ (SEQ ID NO: 6253)5′-CUAGGCUACAACAGGAUUCUAGGtg-3′ (SEQ ID NO: 2226)3′-CAGAUCCGAUGUUGUCCUAAGAUCCAC-5′ (SEQ ID NO: 4240) LDHA-1325 Target:5′-GTCTAGGCTACAACAGGATTCTAGGTG-3′ (SEQ ID NO: 6254)5′-UAGGCUACAACAGGAUUCUAGGUgg-3′ (SEQ ID NO: 2227)3′-AGAUCCGAUGUUGUCCUAAGAUCCACC-5′ (SEQ ID NO: 4241) LDHA-1326 Target:5′-TCTAGGCTACAACAGGATTCTAGGTGG-3′ (SEQ ID NO: 6255)5′-AGGCUACAACAGGAUUCUAGGUGga-3′ (SEQ ID NO: 2228)3′-GAUCCGAUGUUGUCCUAAGAUCCACCU-5′ (SEQ ID NO: 4242) LDHA-1327 Target:5′-CTAGGCTACAACAGGATTCTAGGTGGA-3′ (SEQ ID NO: 6256)5′-GGCUACAACAGGAUUCUAGGUGGag-3′ (SEQ ID NO: 2229)3′-AUCCGAUGUUGUCCUAAGAUCCACCUC-5′ (SEQ ID NO: 4243) LDHA-1328 Target:5′-TAGGCTACAACAGGATTCTAGGTGGAG-3′ (SEQ ID NO: 6257)5′-GCUACAACAGGAUUCUAGGUGGAgg-3′ (SEQ ID NO: 2230)3′-UCCGAUGUUGUCCUAAGAUCCACCUCC-5′ (SEQ ID NO: 4244) LDHA-1329 Target:5′-AGGCTACAACAGGATTCTAGGTGGAGG-3′ (SEQ ID NO: 6258)5′-CUACAACAGGAUUCUAGGUGGAGgt-3′ (SEQ ID NO: 2231)3′-CCGAUGUUGUCCUAAGAUCCACCUCCA-5′ (SEQ ID NO: 4245) LDHA-1330 Target:5′-GGCTACAACAGGATTCTAGGTGGAGGT-3′ (SEQ ID NO: 6259)5′-UACAACAGGAUUCUAGGUGGAGGtt-3′ (SEQ ID NO: 2232)3′-CGAUGUUGUCCUAAGAUCCACCUCCAA-5′ (SEQ ID NO: 4246) LDHA-1331 Target:5′-GCTACAACAGGATTCTAGGTGGAGGTT-3′ (SEQ ID NO: 6260)5′-ACAACAGGAUUCUAGGUGGAGGUtg-3′ (SEQ ID NO: 2233)3′-GAUGUUGUCCUAAGAUCCACCUCCAAC-5′ (SEQ ID NO: 4247) LDHA-1332 Target:5′-CTACAACAGGATTCTAGGTGGAGGTTG-3′ (SEQ ID NO: 6261)5′-CAACAGGAUUCUAGGUGGAGGUUgt-3′ (SEQ ID NO: 2234)3′-AUGUUGUCCUAAGAUCCACCUCCAACA-5′ (SEQ ID NO: 4248) LDHA-1333 Target:5′-TACAACAGGATTCTAGGTGGAGGTTGT-3′ (SEQ ID NO: 6262)5′-AACAGGAUUCUAGGUGGAGGUUGtg-3′ (SEQ ID NO: 2235)3′-UGUUGUCCUAAGAUCCACCUCCAACAC-5′ (SEQ ID NO: 4249) LDHA-1334 Target:5′-ACAACAGGATTCTAGGTGGAGGTTGTG-3′ (SEQ ID NO: 6263)5′-ACAGGAUUCUAGGUGGAGGUUGUgc-3′ (SEQ ID NO: 2236)3′-GUUGUCCUAAGAUCCACCUCCAACACG-5′ (SEQ ID NO: 4250) LDHA-1335 Target:5′-CAACAGGATTCTAGGTGGAGGTTGTGC-3′ (SEQ ID NO: 6264)5′-CAGGAUUCUAGGUGGAGGUUGUGca-3′ (SEQ ID NO: 2237)3′-UUGUCCUAAGAUCCACCUCCAACACGU-5′ (SEQ ID NO: 4251) LDHA-1336 Target:5′-AACAGGATTCTAGGTGGAGGTTGTGCA-3′ (SEQ ID NO: 6265)5′-AGGAUUCUAGGUGGAGGUUGUGCat-3′ (SEQ ID NO: 2238)3′-UGUCCUAAGAUCCACCUCCAACACGUA-5′ (SEQ ID NO: 4252) LDHA-1337 Target:5′-ACAGGATTCTAGGTGGAGGTTGTGCAT-3′ (SEQ ID NO: 6266)5′-GGAUUCUAGGUGGAGGUUGUGCAtg-3′ (SEQ ID NO: 2239)3′-GUCCUAAGAUCCACCUCCAACACGUAC-5′ (SEQ ID NO: 4253) LDHA-1338 Target:5′-CAGGATTCTAGGTGGAGGTTGTGCATG-3′ (SEQ ID NO: 6267)5′-GAUUCUAGGUGGAGGUUGUGCAUgt-3′ (SEQ ID NO: 2240)3′-UCCUAAGAUCCACCUCCAACACGUACA-5′ (SEQ ID NO: 4254) LDHA-1339 Target:5′-AGGATTCTAGGTGGAGGTTGTGCATGT-3′ (SEQ ID NO: 6268)5′-AUUCUAGGUGGAGGUUGUGCAUGtt-3′ (SEQ ID NO: 2241)3′-CCUAAGAUCCACCUCCAACACGUACAA-5′ (SEQ ID NO: 4255) LDHA-1340 Target:5′-GGATTCTAGGTGGAGGTTGTGCATGTT-3′ (SEQ ID NO: 6269)5′-UUCUAGGUGGAGGUUGUGCAUGUtg-3′ (SEQ ID NO: 2242)3′-CUAAGAUCCACCUCCAACACGUACAAC-5′ (SEQ ID NO: 4256) LDHA-1341 Target:5′-GATTCTAGGTGGAGGTTGTGCATGTTG-3′ (SEQ ID NO: 6270)5′-UCUAGGUGGAGGUUGUGCAUGUUgt-3′ (SEQ ID NO: 2243)3′-UAAGAUCCACCUCCAACACGUACAACA-5′ (SEQ ID NO: 4257) LDHA-1342 Target:5′-ATTCTAGGTGGAGGTTGTGCATGTTGT-3′ (SEQ ID NO: 6271)5′-CUAGGUGGAGGUUGUGCAUGUUGtc-3′ (SEQ ID NO: 2244)3′-AAGAUCCACCUCCAACACGUACAACAG-5′ (SEQ ID NO: 4258) LDHA-1343 Target:5′-TTCTAGGTGGAGGTTGTGCATGTTGTC-3′ (SEQ ID NO: 6272)5′-UAGGUGGAGGUUGUGCAUGUUGUcc-3′ (SEQ ID NO: 2245)3′-AGAUCCACCUCCAACACGUACAACAGG-5′ (SEQ ID NO: 4259) LDHA-1344 Target:5′-TCTAGGTGGAGGTTGTGCATGTTGTCC-3′ (SEQ ID NO: 6273)5′-AGGUGGAGGUUGUGCAUGUUGUCct-3′ (SEQ ID NO: 2246)3′-GAUCCACCUCCAACACGUACAACAGGA-5′ (SEQ ID NO: 4260) LDHA-1345 Target:5′-CTAGGTGGAGGTTGTGCATGTTGTCCT-3′ (SEQ ID NO: 6274)5′-GGUGGAGGUUGUGCAUGUUGUCCtt-3′ (SEQ ID NO: 2247)3′-AUCCACCUCCAACACGUACAACAGGAA-5′ (SEQ ID NO: 4261) LDHA-1346 Target:5′-TAGGTGGAGGTTGTGCATGTTGTCCTT-3′ (SEQ ID NO: 6275)5′-GUGGAGGUUGUGCAUGUUGUCCUtt-3′ (SEQ ID NO: 2248)3′-UCCACCUCCAACACGUACAACAGGAAA-5′ (SEQ ID NO: 4262) LDHA-1347 Target:5′-AGGTGGAGGTTGTGCATGTTGTCCTTT-3′ (SEQ ID NO: 6276)5′-UGGAGGUUGUGCAUGUUGUCCUUtt-3′ (SEQ ID NO: 2249)3′-CCACCUCCAACACGUACAACAGGAAAA-5′ (SEQ ID NO: 4263) LDHA-1348 Target:5′-GGTGGAGGTTGTGCATGTTGTCCTTTT-3′ (SEQ ID NO: 6277)5′-GGAGGUUGUGCAUGUUGUCCUUUtt-3′ (SEQ ID NO: 2250)3′-CACCUCCAACACGUACAACAGGAAAAA-5′ (SEQ ID NO: 4264) LDHA-1349 Target:5′-GTGGAGGTTGTGCATGTTGTCCTTTTT-3′ (SEQ ID NO: 6278)5′-GAGGUUGUGCAUGUUGUCCUUUUta-3′ (SEQ ID NO: 2251)3′-ACCUCCAACACGUACAACAGGAAAAAU-5′ (SEQ ID NO: 4265) LDHA-1350 Target:5′-TGGAGGTTGTGCATGTTGTCCTTTTTA-3′ (SEQ ID NO: 6279)5′-AGGUUGUGCAUGUUGUCCUUUUUat-3′ (SEQ ID NO: 2252)3′-CCUCCAACACGUACAACAGGAAAAAUA-5′ (SEQ ID NO: 4266) LDHA-1351 Target:5′-GGAGGTTGTGCATGTTGTCCTTTTTAT-3′ (SEQ ID NO: 6280)5′-GGUUGUGCAUGUUGUCCUUUUUAtc-3′ (SEQ ID NO: 2253)3′-CUCCAACACGUACAACAGGAAAAAUAG-5′ (SEQ ID NO: 4267) LDHA-1352 Target:5′-GAGGTTGTGCATGTTGTCCTTTTTATC-3′ (SEQ ID NO: 6281)5′-GUUGUGCAUGUUGUCCUUUUUAUct-3′ (SEQ ID NO: 2254)3′-UCCAACACGUACAACAGGAAAAAUAGA-5′ (SEQ ID NO: 4268) LDHA-1353 Target:5′-AGGTTGTGCATGTTGTCCTTTTTATCT-3′ (SEQ ID NO: 6282)5′-UUGUGCAUGUUGUCCUUUUUAUCtg-3′ (SEQ ID NO: 2255)3′-CCAACACGUACAACAGGAAAAAUAGAC-5′ (SEQ ID NO: 4269) LDHA-1354 Target:5′-GGTTGTGCATGTTGTCCTTTTTATCTG-3′ (SEQ ID NO: 6283)5′-UGUGCAUGUUGUCCUUUUUAUCUga-3′ (SEQ ID NO: 2256)3′-CAACACGUACAACAGGAAAAAUAGACU-5′ (SEQ ID NO: 4270) LDHA-1355 Target:5′-GTTGTGCATGTTGTCCTTTTTATCTGA-3′ (SEQ ID NO: 6284)5′-GUGCAUGUUGUCCUUUUUAUCUGat-3′ (SEQ ID NO: 2257)3′-AACACGUACAACAGGAAAAAUAGACUA-5′ (SEQ ID NO: 4271) LDHA-1356 Target:5′-TTGTGCATGTTGTCCTTTTTATCTGAT-3′ (SEQ ID NO: 6285)5′-UGCAUGUUGUCCUUUUUAUCUGAtc-3′ (SEQ ID NO: 2258)3′-ACACGUACAACAGGAAAAAUAGACUAG-5′ (SEQ ID NO: 4272) LDHA-1357 Target:5′-TGTGCATGTTGTCCTTTTTATCTGATC-3′ (SEQ ID NO: 6286)5′-GCAUGUUGUCCUUUUUAUCUGAUct-3′ (SEQ ID NO: 2259)3′-CACGUACAACAGGAAAAAUAGACUAGA-5′ (SEQ ID NO: 4273) LDHA-1358 Target:5′-GTGCATGTTGTCCTTTTTATCTGATCT-3′ (SEQ ID NO: 6287)5′-UGUCCUUUUUAUCUGAUCUGUGAtt-3′ (SEQ ID NO: 2260)3′-CAACAGGAAAAAUAGACUAGACACUAA-5′ (SEQ ID NO: 4274) LDHA-1364 Target:5′-GTTGTCCTTTTTATCTGATCTGTGATT-3′ (SEQ ID NO: 6288)5′-UUUUUAUCUGAUCUGUGAUUAAAgc-3′ (SEQ ID NO: 2261)3′-GGAAAAAUAGACUAGACACUAAUUUCG-5′ (SEQ ID NO: 4275) LDHA-1369 Target:5′-CCTTTTTATCTGATCTGTGATTAAAGC-3′ (SEQ ID NO: 6289)5′-UAUCUGAUCUGUGAUUAAAGCAGta-3′ (SEQ ID NO: 2262)3′-AAAUAGACUAGACACUAAUUUCGUCAU-5′ (SEQ ID NO: 4276) LDHA-1373 Target:5′-TTTATCTGATCTGTGATTAAAGCAGTA-3′ (SEQ ID NO: 6290)5′-AUCUGAUCUGUGAUUAAAGCAGUaa-3′ (SEQ ID NO: 2263)3′-AAUAGACUAGACACUAAUUUCGUCAUU-5′ (SEQ ID NO: 4277) LDHA-1374 Target:5′-TTATCTGATCTGTGATTAAAGCAGTAA-3′ (SEQ ID NO: 6291)5′-UCUGAUCUGUGAUUAAAGCAGUAat-3′ (SEQ ID NO: 2264)3′-AUAGACUAGACACUAAUUUCGUCAUUA-5′ (SEQ ID NO: 4278) LDHA-1375 Target:5′-TATCTGATCTGTGATTAAAGCAGTAAT-3′ (SEQ ID NO: 6292)5′-CUGAUCUGUGAUUAAAGCAGUAAta-3′ (SEQ ID NO: 2265)3′-UAGACUAGACACUAAUUUCGUCAUUAU-5′ (SEQ ID NO: 4279) LDHA-1376 Target:5′-ATCTGATCTGTGATTAAAGCAGTAATA-3′ (SEQ ID NO: 6293)5′-UGAUCUGUGAUUAAAGCAGUAAUat-3′ (SEQ ID NO: 2266)3′-AGACUAGACACUAAUUUCGUCAUUAUA-5′ (SEQ ID NO: 4280) LDHA-1377 Target:5′-TCTGATCTGTGATTAAAGCAGTAATAT-3′ (SEQ ID NO: 6294)5′-GAUCUGUGAUUAAAGCAGUAAUAtt-3′ (SEQ ID NO: 2267)3′-GACUAGACACUAAUUUCGUCAUUAUAA-5′ (SEQ ID NO: 4281) LDHA-1378 Target:5′-CTGATCTGTGATTAAAGCAGTAATATT-3′ (SEQ ID NO: 6295)5′-AUCUGUGAUUAAAGCAGUAAUAUtt-3′ (SEQ ID NO: 2268)3′-ACUAGACACUAAUUUCGUCAUUAUAAA-5′ (SEQ ID NO: 4282) LDHA-1379 Target:5′-TGATCTGTGATTAAAGCAGTAATATTT-3′ (SEQ ID NO: 6296)5′-UCUGUGAUUAAAGCAGUAAUAUUtt-3′ (SEQ ID NO: 2269)3′-CUAGACACUAAUUUCGUCAUUAUAAAA-5′ (SEQ ID NO: 4283) LDHA-1380 Target:5′-GATCTGTGATTAAAGCAGTAATATTTT-3′ (SEQ ID NO: 6297)5′-CUGUGAUUAAAGCAGUAAUAUUUta-3′ (SEQ ID NO: 2270)3′-UAGACACUAAUUUCGUCAUUAUAAAAU-5′ (SEQ ID NO: 4284) LDHA-1381 Target:5′-ATCTGTGATTAAAGCAGTAATATTTTA-3′ (SEQ ID NO: 6298)5′-UGUGAUUAAAGCAGUAAUAUUUUaa-3′ (SEQ ID NO: 2271)3′-AGACACUAAUUUCGUCAUUAUAAAAUU-5′ (SEQ ID NO: 4285) LDHA-1382 Target:5′-TCTGTGATTAAAGCAGTAATATTTTAA-3′ (SEQ ID NO: 6299)5′-GUGAUUAAAGCAGUAAUAUUUUAag-3′ (SEQ ID NO: 2272)3′-GACACUAAUUUCGUCAUUAUAAAAUUC-5′ (SEQ ID NO: 4286) LDHA-1383 Target:5′-CTGTGATTAAAGCAGTAATATTTTAAG-3′ (SEQ ID NO: 6300)5′-UGAUUAAAGCAGUAAUAUUUUAAga-3′ (SEQ ID NO: 2273)3′-ACACUAAUUUCGUCAUUAUAAAAUUCU-5′ (SEQ ID NO: 4287) LDHA-1384 Target:5′-TGTGATTAAAGCAGTAATATTTTAAGA-3′ (SEQ ID NO: 6301)5′-GAUUAAAGCAGUAAUAUUUUAAGat-3′ (SEQ ID NO: 2274)3′-CACUAAUUUCGUCAUUAUAAAAUUCUA-5′ (SEQ ID NO: 4288) LDHA-1385 Target:5′-GTGATTAAAGCAGTAATATTTTAAGAT-3′ (SEQ ID NO: 6302)5′-AUUAAAGCAGUAAUAUUUUAAGAtg-3′ (SEQ ID NO: 2275)3′-ACUAAUUUCGUCAUUAUAAAAUUCUAC-5′ (SEQ ID NO: 4289) LDHA-1386 Target:5′-TGATTAAAGCAGTAATATTTTAAGATG-3′ (SEQ ID NO: 6303)5′-UUAAAGCAGUAAUAUUUUAAGAUgg-3′ (SEQ ID NO: 2276)3′-CUAAUUUCGUCAUUAUAAAAUUCUACC-5′ (SEQ ID NO: 4290) LDHA-1387 Target:5′-GATTAAAGCAGTAATATTTTAAGATGG-3′ (SEQ ID NO: 6304)5′-UAAAGCAGUAAUAUUUUAAGAUGga-3′ (SEQ ID NO: 2277)3′-UAAUUUCGUCAUUAUAAAAUUCUACCU-5′ (SEQ ID NO: 4291) LDHA-1388 Target:5′-ATTAAAGCAGTAATATTTTAAGATGGA-3′ (SEQ ID NO: 6305)5′-AAAGCAGUAAUAUUUUAAGAUGGac-3′ (SEQ ID NO: 2278)3′-AAUUUCGUCAUUAUAAAAUUCUACCUG-5′ (SEQ ID NO: 4292) LDHA-1389 Target:5′-TTAAAGCAGTAATATTTTAAGATGGAC-3′ (SEQ ID NO: 6306)5′-AAGCAGUAAUAUUUUAAGAUGGAct-3′ (SEQ ID NO: 2279)3′-AUUUCGUCAUUAUAAAAUUCUACCUGA-5′ (SEQ ID NO: 4293) LDHA-1390 Target:5′-TAAAGCAGTAATATTTTAAGATGGACT-3′ (SEQ ID NO: 6307)5′-AGCAGUAAUAUUUUAAGAUGGACtg-3′ (SEQ ID NO: 2280)3′-UUUCGUCAUUAUAAAAUUCUACCUGAC-5′ (SEQ ID NO: 4294) LDHA-1391 Target:5′-AAAGCAGTAATATTTTAAGATGGACTG-3′ (SEQ ID NO: 6308)5′-GCAGUAAUAUUUUAAGAUGGACUgg-3′ (SEQ ID NO: 2281)3′-UUCGUCAUUAUAAAAUUCUACCUGACC-5′ (SEQ ID NO: 4295) LDHA-1392 Target:5′-AAGCAGTAATATTTTAAGATGGACTGG-3′ (SEQ ID NO: 6309)5′-AGUAAUAUUUUAAGAUGGACUGGga-3′ (SEQ ID NO: 2282)3′-CGUCAUUAUAAAAUUCUACCUGACCCU-5′ (SEQ ID NO: 4296) LDHA-1394 Target:5′-GCAGTAATATTTTAAGATGGACTGGGA-3′ (SEQ ID NO: 6310)5′-GUAAUAUUUUAAGAUGGACUGGGaa-3′ (SEQ ID NO: 2283)3′-GUCAUUAUAAAAUUCUACCUGACCCUU-5′ (SEQ ID NO: 4297) LDHA-1395 Target:5′-CAGTAATATTTTAAGATGGACTGGGAA-3′ (SEQ ID NO: 6311)5′-UAAUAUUUUAAGAUGGACUGGGAaa-3′ (SEQ ID NO: 2284)3′-UCAUUAUAAAAUUCUACCUGACCCUUU-5′ (SEQ ID NO: 4298) LDHA-1396 Target:5′-AGTAATATTTTAAGATGGACTGGGAAA-3′ (SEQ ID NO: 6312)5′-AAUAUUUUAAGAUGGACUGGGAAaa-3′ (SEQ ID NO: 2285)3′-CAUUAUAAAAUUCUACCUGACCCUUUU-5′ (SEQ ID NO: 4299) LDHA-1397 Target:5′-GTAATATTTTAAGATGGACTGGGAAAA-3′ (SEQ ID NO: 6313)5′-AUAUUUUAAGAUGGACUGGGAAAaa-3′ (SEQ ID NO: 2286)3′-AUUAUAAAAUUCUACCUGACCCUUUUU-5′ (SEQ ID NO: 4300) LDHA-1398 Target:5′-TAATATTTTAAGATGGACTGGGAAAAA-3′ (SEQ ID NO: 6314)5′-UAUUUUAAGAUGGACUGGGAAAAac-3′ (SEQ ID NO: 2287)3′-UUAUAAAAUUCUACCUGACCCUUUUUG-5′ (SEQ ID NO: 4301) LDHA-1399 Target:5′-AATATTTTAAGATGGACTGGGAAAAAC-3′ (SEQ ID NO: 6315)5′-AUUUUAAGAUGGACUGGGAAAAAca-3′ (SEQ ID NO: 2288)3′-UAUAAAAUUCUACCUGACCCUUUUUGU-5′ (SEQ ID NO: 4302) LDHA-1400 Target:5′-ATATTTTAAGATGGACTGGGAAAAACA-3′ (SEQ ID NO: 6316)5′-UUUUAAGAUGGACUGGGAAAAACat-3′ (SEQ ID NO: 2289)3′-AUAAAAUUCUACCUGACCCUUUUUGUA-5′ (SEQ ID NO: 4303) LDHA-1401 Target:5′-TATTTTAAGATGGACTGGGAAAAACAT-3′ (SEQ ID NO: 6317)5′-UUUAAGAUGGACUGGGAAAAACAtc-3′ (SEQ ID NO: 2290)3′-UAAAAUUCUACCUGACCCUUUUUGUAG-5′ (SEQ ID NO: 4304) LDHA-1402 Target:5′-ATTTTAAGATGGACTGGGAAAAACATC-3′ (SEQ ID NO: 6318)5′-UUAAGAUGGACUGGGAAAAACAUca-3′ (SEQ ID NO: 2291)3′-AAAAUUCUACCUGACCCUUUUUGUAGU-5′ (SEQ ID NO: 4305) LDHA-1403 Target:5′-TTTTAAGATGGACTGGGAAAAACATCA-3′ (SEQ ID NO: 6319)5′-UAAGAUGGACUGGGAAAAACAUCaa-3′ (SEQ ID NO: 2292)3′-AAAUUCUACCUGACCCUUUUUGUAGUU-5′ (SEQ ID NO: 4306) LDHA-1404 Target:5′-TTTAAGATGGACTGGGAAAAACATCAA-3′ (SEQ ID NO: 6320)5′-AAGAUGGACUGGGAAAAACAUCAac-3′ (SEQ ID NO: 2293)3′-AAUUCUACCUGACCCUUUUUGUAGUUG-5′ (SEQ ID NO: 4307) LDHA-1405 Target:5′-TTAAGATGGACTGGGAAAAACATCAAC-3′ (SEQ ID NO: 6321)5′-AGAUGGACUGGGAAAAACAUCAAct-3′ (SEQ ID NO: 2294)3′-AUUCUACCUGACCCUUUUUGUAGUUGA-5′ (SEQ ID NO: 4308) LDHA-1406 Target:5′-TAAGATGGACTGGGAAAAACATCAACT-3′ (SEQ ID NO: 6322)5′-GAUGGACUGGGAAAAACAUCAACtc-3′ (SEQ ID NO: 2295)3′-UUCUACCUGACCCUUUUUGUAGUUGAG-5′ (SEQ ID NO: 4309) LDHA-1407 Target:5′-AAGATGGACTGGGAAAAACATCAACTC-3′ (SEQ ID NO: 6323)5′-AUGGACUGGGAAAAACAUCAACUcc-3′ (SEQ ID NO: 2296)3′-UCUACCUGACCCUUUUUGUAGUUGAGG-5′ (SEQ ID NO: 4310) LDHA-1408 Target:5′-AGATGGACTGGGAAAAACATCAACTCC-3′ (SEQ ID NO: 6324)5′-UGGACUGGGAAAAACAUCAACUCct-3′ (SEQ ID NO: 2297)3′-CUACCUGACCCUUUUUGUAGUUGAGGA-5′ (SEQ ID NO: 4311) LDHA-1409 Target:5′-GATGGACTGGGAAAAACATCAACTCCT-3′ (SEQ ID NO: 6325)5′-GGACUGGGAAAAACAUCAACUCCtg-3′ (SEQ ID NO: 2298)3′-UACCUGACCCUUUUUGUAGUUGAGGAC-5′ (SEQ ID NO: 4312) LDHA-1410 Target:5′-ATGGACTGGGAAAAACATCAACTCCTG-3′ (SEQ ID NO: 6326)5′-GACUGGGAAAAACAUCAACUCCUga-3′ (SEQ ID NO: 2299)3′-ACCUGACCCUUUUUGUAGUUGAGGACU-5′ (SEQ ID NO: 4313) LDHA-1411 Target:5′-TGGACTGGGAAAAACATCAACTCCTGA-3′ (SEQ ID NO: 6327)5′-ACUGGGAAAAACAUCAACUCCUGaa-3′ (SEQ ID NO: 2300)3′-CCUGACCCUUUUUGUAGUUGAGGACUU-5′ (SEQ ID NO: 4314) LDHA-1412 Target:5′-GGACTGGGAAAAACATCAACTCCTGAA-3′ (SEQ ID NO: 6328)5′-CUGGGAAAAACAUCAACUCCUGAag-3′ (SEQ ID NO: 2301)3′-CUGACCCUUUUUGUAGUUGAGGACUUC-5′ (SEQ ID NO: 4315) LDHA-1413 Target:5′-GACTGGGAAAAACATCAACTCCTGAAG-3′ (SEQ ID NO: 6329)5′-UGGGAAAAACAUCAACUCCUGAAgt-3′ (SEQ ID NO: 2302)3′-UGACCCUUUUUGUAGUUGAGGACUUCA-5′ (SEQ ID NO: 4316) LDHA-1414 Target:5′-ACTGGGAAAAACATCAACTCCTGAAGT-3′ (SEQ ID NO: 6330)5′-GGGAAAAACAUCAACUCCUGAAGtt-3′ (SEQ ID NO: 2303)3′-GACCCUUUUUGUAGUUGAGGACUUCAA-5′ (SEQ ID NO: 4317) LDHA-1415 Target:5′-CTGGGAAAAACATCAACTCCTGAAGTT-3′ (SEQ ID NO: 6331)5′-GGAAAAACAUCAACUCCUGAAGUta-3′ (SEQ ID NO: 2304)3′-ACCCUUUUUGUAGUUGAGGACUUCAAU-5′ (SEQ ID NO: 4318) LDHA-1416 Target:5′-TGGGAAAAACATCAACTCCTGAAGTTA-3′ (SEQ ID NO: 6332)5′-GAAAAACAUCAACUCCUGAAGUUag-3′ (SEQ ID NO: 2305)3′-CCCUUUUUGUAGUUGAGGACUUCAAUC-5′ (SEQ ID NO: 4319) LDHA-1417 Target:5′-GGGAAAAACATCAACTCCTGAAGTTAG-3′ (SEQ ID NO: 6333)5′-AAAAACAUCAACUCCUGAAGUUAga-3′ (SEQ ID NO: 2306)3′-CCUUUUUGUAGUUGAGGACUUCAAUCU-5′ (SEQ ID NO: 4320) LDHA-1418 Target:5′-GGAAAAACATCAACTCCTGAAGTTAGA-3′ (SEQ ID NO: 6334)5′-AAAACAUCAACUCCUGAAGUUAGaa-3′ (SEQ ID NO: 2307)3′-CUUUUUGUAGUUGAGGACUUCAAUCUU-5′ (SEQ ID NO: 4321) LDHA-1419 Target:5′-GAAAAACATCAACTCCTGAAGTTAGAA-3′ (SEQ ID NO: 6335)5′-AAACAUCAACUCCUGAAGUUAGAaa-3′ (SEQ ID NO: 2308)3′-UUUUUGUAGUUGAGGACUUCAAUCUUU-5′ (SEQ ID NO: 4322) LDHA-1420 Target:5′-AAAAACATCAACTCCTGAAGTTAGAAA-3′ (SEQ ID NO: 6336)5′-AACAUCAACUCCUGAAGUUAGAAat-3′ (SEQ ID NO: 2309)3′-UUUUGUAGUUGAGGACUUCAAUCUUUA-5′ (SEQ ID NO: 4323) LDHA-1421 Target:5′-AAAACATCAACTCCTGAAGTTAGAAAT-3′ (SEQ ID NO: 6337)5′-ACAUCAACUCCUGAAGUUAGAAAta-3′ (SEQ ID NO: 2310)3′-UUUGUAGUUGAGGACUUCAAUCUUUAU-5′ (SEQ ID NO: 4324) LDHA-1422 Target:5′-AAACATCAACTCCTGAAGTTAGAAATA-3′ (SEQ ID NO: 6338)5′-CAUCAACUCCUGAAGUUAGAAAUaa-3′ (SEQ ID NO: 2311)3′-UUGUAGUUGAGGACUUCAAUCUUUAUU-5′ (SEQ ID NO: 4325) LDHA-1423 Target:5′-AACATCAACTCCTGAAGTTAGAAATAA-3′ (SEQ ID NO: 6339)5′-AUCAACUCCUGAAGUUAGAAAUAag-3′ (SEQ ID NO: 2312)3′-UGUAGUUGAGGACUUCAAUCUUUAUUC-5′ (SEQ ID NO: 4326) LDHA-1424 Target:5′-ACATCAACTCCTGAAGTTAGAAATAAG-3′ (SEQ ID NO: 6340)5′-UCAACUCCUGAAGUUAGAAAUAAga-3′ (SEQ ID NO: 2313)3′-GUAGUUGAGGACUUCAAUCUUUAUUCU-5′ (SEQ ID NO: 4327) LDHA-1425 Target:5′-CATCAACTCCTGAAGTTAGAAATAAGA-3′ (SEQ ID NO: 6341)5′-CAACUCCUGAAGUUAGAAAUAAGaa-3′ (SEQ ID NO: 2314)3′-UAGUUGAGGACUUCAAUCUUUAUUCUU-5′ (SEQ ID NO: 4328) LDHA-1426 Target:5′-ATCAACTCCTGAAGTTAGAAATAAGAA-3′ (SEQ ID NO: 6342)5′-CUCCUGAAGUUAGAAAUAAGAAUgg-3′ (SEQ ID NO: 2315)3′-UUGAGGACUUCAAUCUUUAUUCUUACC-5′ (SEQ ID NO: 4329) LDHA-1429 Target:5′-AACTCCTGAAGTTAGAAATAAGAATGG-3′ (SEQ ID NO: 6343)5′-UCCUGAAGUUAGAAAUAAGAAUGgt-3′ (SEQ ID NO: 2316)3′-UGAGGACUUCAAUCUUUAUUCUUACCA-5′ (SEQ ID NO: 4330) LDHA-1430 Target:5′-ACTCCTGAAGTTAGAAATAAGAATGGT-3′ (SEQ ID NO: 6344)5′-CCUGAAGUUAGAAAUAAGAAUGGtt-3′ (SEQ ID NO: 2317)3′-GAGGACUUCAAUCUUUAUUCUUACCAA-5′ (SEQ ID NO: 4331) LDHA-1431 Target:5′-CTCCTGAAGTTAGAAATAAGAATGGTT-3′ (SEQ ID NO: 6345)5′-CUGAAGUUAGAAAUAAGAAUGGUtt-3′ (SEQ ID NO: 2318)3′-AGGACUUCAAUCUUUAUUCUUACCAAA-5′ (SEQ ID NO: 4332) LDHA-1432 Target:5′-TCCTGAAGTTAGAAATAAGAATGGTTT-3′ (SEQ ID NO: 6346)5′-UGAAGUUAGAAAUAAGAAUGGUUtg-3′ (SEQ ID NO: 2319)3′-GGACUUCAAUCUUUAUUCUUACCAAAC-5′ (SEQ ID NO: 4333) LDHA-1433 Target:5′-CCTGAAGTTAGAAATAAGAATGGTTTG-3′ (SEQ ID NO: 6347)5′-GAAGUUAGAAAUAAGAAUGGUUUgt-3′ (SEQ ID NO: 2320)3′-GACUUCAAUCUUUAUUCUUACCAAACA-5′ (SEQ ID NO: 4334) LDHA-1434 Target:5′-CTGAAGTTAGAAATAAGAATGGTTTGT-3′ (SEQ ID NO: 6348)5′-AAGUUAGAAAUAAGAAUGGUUUGta-3′ (SEQ ID NO: 2321)3′-ACUUCAAUCUUUAUUCUUACCAAACAU-5′ (SEQ ID NO: 4335) LDHA-1435 Target:5′-TGAAGTTAGAAATAAGAATGGTTTGTA-3′ (SEQ ID NO: 6349)5′-AGUUAGAAAUAAGAAUGGUUUGUaa-3′ (SEQ ID NO: 2322)3′-CUUCAAUCUUUAUUCUUACCAAACAUU-5′ (SEQ ID NO: 4336) LDHA-1436 Target:5′-GAAGTTAGAAATAAGAATGGTTTGTAA-3′ (SEQ ID NO: 6350)5′-GUUAGAAAUAAGAAUGGUUUGUAaa-3′ (SEQ ID NO: 2323)3′-UUCAAUCUUUAUUCUUACCAAACAUUU-5′ (SEQ ID NO: 4337) LDHA-1437 Target:5′-AAGTTAGAAATAAGAATGGTTTGTAAA-3′ (SEQ ID NO: 6351)5′-UUAGAAAUAAGAAUGGUUUGUAAaa-3′ (SEQ ID NO: 2324)3′-UCAAUCUUUAUUCUUACCAAACAUUUU-5′ (SEQ ID NO: 4338) LDHA-1438 Target:5′-AGTTAGAAATAAGAATGGTTTGTAAAA-3′ (SEQ ID NO: 6352)5′-UAGAAAUAAGAAUGGUUUGUAAAat-3′ (SEQ ID NO: 2325)3′-CAAUCUUUAUUCUUACCAAACAUUUUA-5′ (SEQ ID NO: 4339) LDHA-1439 Target:5′-GTTAGAAATAAGAATGGTTTGTAAAAT-3′ (SEQ ID NO: 6353)5′-AGAAAUAAGAAUGGUUUGUAAAAtc-3′ (SEQ ID NO: 2326)3′-AAUCUUUAUUCUUACCAAACAUUUUAG-5′ (SEQ ID NO: 4340) LDHA-1440 Target:5′-TTAGAAATAAGAATGGTTTGTAAAATC-3′ (SEQ ID NO: 6354)5′-GAAAUAAGAAUGGUUUGUAAAAUcc-3′ (SEQ ID NO: 2327)3′-AUCUUUAUUCUUACCAAACAUUUUAGG-5′ (SEQ ID NO: 4341) LDHA-1441 Target:5′-TAGAAATAAGAATGGTTTGTAAAATCC-3′ (SEQ ID NO: 6355)5′-AAAUAAGAAUGGUUUGUAAAAUCca-3′ (SEQ ID NO: 2328)3′-UCUUUAUUCUUACCAAACAUUUUAGGU-5′ (SEQ ID NO: 4342) LDHA-1442 Target:5′-AGAAATAAGAATGGTTTGTAAAATCCA-3′ (SEQ ID NO: 6356)5′-AAUAAGAAUGGUUUGUAAAAUCCac-3′ (SEQ ID NO: 2329)3′-CUUUAUUCUUACCAAACAUUUUAGGUG-5′ (SEQ ID NO: 4343) LDHA-1443 Target:5′-GAAATAAGAATGGTTTGTAAAATCCAC-3′ (SEQ ID NO: 6357)5′-AUAAGAAUGGUUUGUAAAAUCCAca-3′ (SEQ ID NO: 2330)3′-UUUAUUCUUACCAAACAUUUUAGGUGU-5′ (SEQ ID NO: 4344) LDHA-1444 Target:5′-AAATAAGAATGGTTTGTAAAATCCACA-3′ (SEQ ID NO: 6358)5′-UAAGAAUGGUUUGUAAAAUCCACag-3′ (SEQ ID NO: 2331)3′-UUAUUCUUACCAAACAUUUUAGGUGUC-5′ (SEQ ID NO: 4345) LDHA-1445 Target:5′-AATAAGAATGGTTTGTAAAATCCACAG-3′ (SEQ ID NO: 6359)5′-AAGAAUGGUUUGUAAAAUCCACAgc-3′ (SEQ ID NO: 2332)3′-UAUUCUUACCAAACAUUUUAGGUGUCG-5′ (SEQ ID NO: 4346) LDHA-1446 Target:5′-ATAAGAATGGTTTGTAAAATCCACAGC-3′ (SEQ ID NO: 6360)5′-AGAAUGGUUUGUAAAAUCCACAGct-3′ (SEQ ID NO: 2333)3′-AUUCUUACCAAACAUUUUAGGUGUCGA-5′ (SEQ ID NO: 4347) LDHA-1447 Target:5′-TAAGAATGGTTTGTAAAATCCACAGCT-3′ (SEQ ID NO: 6361)5′-GAAUGGUUUGUAAAAUCCACAGCta-3′ (SEQ ID NO: 2334)3′-UUCUUACCAAACAUUUUAGGUGUCGAU-5′ (SEQ ID NO: 4348) LDHA-1448 Target:5′-AAGAATGGTTTGTAAAATCCACAGCTA-3′ (SEQ ID NO: 6362)5′-AAUGGUUUGUAAAAUCCACAGCUat-3′ (SEQ ID NO: 2335)3′-UCUUACCAAACAUUUUAGGUGUCGAUA-5′ (SEQ ID NO: 4349) LDHA-1449 Target:5′-AGAATGGTTTGTAAAATCCACAGCTAT-3′ (SEQ ID NO: 6363)5′-AUGGUUUGUAAAAUCCACAGCUAta-3′ (SEQ ID NO: 2336)3′-CUUACCAAACAUUUUAGGUGUCGAUAU-5′ (SEQ ID NO: 4350) LDHA-1450 Target:5′-GAATGGTTTGTAAAATCCACAGCTATA-3′ (SEQ ID NO: 6364)5′-UGGUUUGUAAAAUCCACAGCUAUat-3′ (SEQ ID NO: 2337)3′-UUACCAAACAUUUUAGGUGUCGAUAUA-5′ (SEQ ID NO: 4351) LDHA-1451 Target:5′-AATGGTTTGTAAAATCCACAGCTATAT-3′ (SEQ ID NO: 6365)5′-GGUUUGUAAAAUCCACAGCUAUAtc-3′ (SEQ ID NO: 2338)3′-UACCAAACAUUUUAGGUGUCGAUAUAG-5′ (SEQ ID NO: 4352) LDHA-1452 Target:5′-ATGGTTTGTAAAATCCACAGCTATATC-3′ (SEQ ID NO: 6366)5′-GUUUGUAAAAUCCACAGCUAUAUcc-3′ (SEQ ID NO: 2339)3′-ACCAAACAUUUUAGGUGUCGAUAUAGG-5′ (SEQ ID NO: 4353) LDHA-1453 Target:5′-TGGTTTGTAAAATCCACAGCTATATCC-3′ (SEQ ID NO: 6367)5′-UUUGUAAAAUCCACAGCUAUAUCct-3′ (SEQ ID NO: 2340)3′-CCAAACAUUUUAGGUGUCGAUAUAGGA-5′ (SEQ ID NO: 4354) LDHA-1454 Target:5′-GGTTTGTAAAATCCACAGCTATATCCT-3′ (SEQ ID NO: 6368)5′-UUGUAAAAUCCACAGCUAUAUCCtg-3′ (SEQ ID NO: 2341)3′-CAAACAUUUUAGGUGUCGAUAUAGGAC-5′ (SEQ ID NO: 4355) LDHA-1455 Target:5′-GTTTGTAAAATCCACAGCTATATCCTG-3′ (SEQ ID NO: 6369)5′-UGUAAAAUCCACAGCUAUAUCCUga-3′ (SEQ ID NO: 2342)3′-AAACAUUUUAGGUGUCGAUAUAGGACU-5′ (SEQ ID NO: 4356) LDHA-1456 Target:5′-TTTGTAAAATCCACAGCTATATCCTGA-3′ (SEQ ID NO: 6370)5′-GUAAAAUCCACAGCUAUAUCCUGat-3′ (SEQ ID NO: 2343)3′-AACAUUUUAGGUGUCGAUAUAGGACUA-5′ (SEQ ID NO: 4357) LDHA-1457 Target:5′-TTGTAAAATCCACAGCTATATCCTGAT-3′ (SEQ ID NO: 6371)5′-UAAAAUCCACAGCUAUAUCCUGAtg-3′ (SEQ ID NO: 2344)3′-ACAUUUUAGGUGUCGAUAUAGGACUAC-5′ (SEQ ID NO: 4358) LDHA-1458 Target:5′-TGTAAAATCCACAGCTATATCCTGATG-3′ (SEQ ID NO: 6372)5′-AAAAUCCACAGCUAUAUCCUGAUgc-3′ (SEQ ID NO: 2345)3′-CAUUUUAGGUGUCGAUAUAGGACUACG-5′ (SEQ ID NO: 4359) LDHA-1459 Target:5′-GTAAAATCCACAGCTATATCCTGATGC-3′ (SEQ ID NO: 6373)5′-AAAUCCACAGCUAUAUCCUGAUGct-3′ (SEQ ID NO: 2346)3′-AUUUUAGGUGUCGAUAUAGGACUACGA-5′ (SEQ ID NO: 4360) LDHA-1460 Target:5′-TAAAATCCACAGCTATATCCTGATGCT-3′ (SEQ ID NO: 6374)5′-AAUCCACAGCUAUAUCCUGAUGCtg-3′ (SEQ ID NO: 2347)3′-UUUUAGGUGUCGAUAUAGGACUACGAC-5′ (SEQ ID NO: 4361) LDHA-1461 Target:5′-AAAATCCACAGCTATATCCTGATGCTG-3′ (SEQ ID NO: 6375)5′-AUCCACAGCUAUAUCCUGAUGCUgg-3′ (SEQ ID NO: 2348)3′-UUUAGGUGUCGAUAUAGGACUACGACC-5′ (SEQ ID NO: 4362) LDHA-1462 Target:5′-AAATCCACAGCTATATCCTGATGCTGG-3′ (SEQ ID NO: 6376)5′-UCCACAGCUAUAUCCUGAUGCUGga-3′ (SEQ ID NO: 2349)3′-UUAGGUGUCGAUAUAGGACUACGACCU-5′ (SEQ ID NO: 4363) LDHA-1463 Target:5′-AATCCACAGCTATATCCTGATGCTGGA-3′ (SEQ ID NO: 6377)5′-CCACAGCUAUAUCCUGAUGCUGGat-3′ (SEQ ID NO: 2350)3′-UAGGUGUCGAUAUAGGACUACGACCUA-5′ (SEQ ID NO: 4364) LDHA-1464 Target:5′-ATCCACAGCTATATCCTGATGCTGGAT-3′ (SEQ ID NO: 6378)5′-CACAGCUAUAUCCUGAUGCUGGAtg-3′ (SEQ ID NO: 2351)3′-AGGUGUCGAUAUAGGACUACGACCUAC-5′ (SEQ ID NO: 4365) LDHA-1465 Target:5′-TCCACAGCTATATCCTGATGCTGGATG-3′ (SEQ ID NO: 6379)5′-ACAGCUAUAUCCUGAUGCUGGAUgg-3′ (SEQ ID NO: 2352)3′-GGUGUCGAUAUAGGACUACGACCUACC-5′ (SEQ ID NO: 4366) LDHA-1466 Target:5′-CCACAGCTATATCCTGATGCTGGATGG-3′ (SEQ ID NO: 6380)5′-CAGCUAUAUCCUGAUGCUGGAUGgt-3′ (SEQ ID NO: 2353)3′-GUGUCGAUAUAGGACUACGACCUACCA-5′ (SEQ ID NO: 4367) LDHA-1467 Target:5′-CACAGCTATATCCTGATGCTGGATGGT-3′ (SEQ ID NO: 6381)5′-AGCUAUAUCCUGAUGCUGGAUGGta-3′ (SEQ ID NO: 2354)3′-UGUCGAUAUAGGACUACGACCUACCAU-5′ (SEQ ID NO: 4368) LDHA-1468 Target:5′-ACAGCTATATCCTGATGCTGGATGGTA-3′ (SEQ ID NO: 6382)5′-GCUAUAUCCUGAUGCUGGAUGGUat-3′ (SEQ ID NO: 2355)3′-GUCGAUAUAGGACUACGACCUACCAUA-5′ (SEQ ID NO: 4369) LDHA-1469 Target:5′-CAGCTATATCCTGATGCTGGATGGTAT-3′ (SEQ ID NO: 6383)5′-CUAUAUCCUGAUGCUGGAUGGUAtt-3′ (SEQ ID NO: 2356)3′-UCGAUAUAGGACUACGACCUACCAUAA-5′ (SEQ ID NO: 4370) LDHA-1470 Target:5′-AGCTATATCCTGATGCTGGATGGTATT-3′ (SEQ ID NO: 6384)5′-UAUAUCCUGAUGCUGGAUGGUAUta-3′ (SEQ ID NO: 2357)3′-CGAUAUAGGACUACGACCUACCAUAAU-5′ (SEQ ID NO: 4371) LDHA-1471 Target:5′-GCTATATCCTGATGCTGGATGGTATTA-3′ (SEQ ID NO: 6385)5′-AUAUCCUGAUGCUGGAUGGUAUUaa-3′ (SEQ ID NO: 2358)3′-GAUAUAGGACUACGACCUACCAUAAUU-5′ (SEQ ID NO: 4372) LDHA-1472 Target:5′-CTATATCCTGATGCTGGATGGTATTAA-3′ (SEQ ID NO: 6386)5′-UAUCCUGAUGCUGGAUGGUAUUAat-3′ (SEQ ID NO: 2359)3′-AUAUAGGACUACGACCUACCAUAAUUA-5′ (SEQ ID NO: 4373) LDHA-1473 Target:5′-TATATCCTGATGCTGGATGGTATTAAT-3′ (SEQ ID NO: 6387)5′-AUCCUGAUGCUGGAUGGUAUUAAtc-3′ (SEQ ID NO: 2360)3′-UAUAGGACUACGACCUACCAUAAUUAG-5′ (SEQ ID NO: 4374) LDHA-1474 Target:5′-ATATCCTGATGCTGGATGGTATTAATC-3′ (SEQ ID NO: 6388)5′-UCCUGAUGCUGGAUGGUAUUAAUct-3′ (SEQ ID NO: 2361)3′-AUAGGACUACGACCUACCAUAAUUAGA-5′ (SEQ ID NO: 4375) LDHA-1475 Target:5′-TATCCTGATGCTGGATGGTATTAATCT-3′ (SEQ ID NO: 6389)5′-CCUGAUGCUGGAUGGUAUUAAUCtt-3′ (SEQ ID NO: 2362)3′-UAGGACUACGACCUACCAUAAUUAGAA-5′ (SEQ ID NO: 4376) LDHA-1476 Target:5′-ATCCTGATGCTGGATGGTATTAATCTT-3′ (SEQ ID NO: 6390)5′-CUGAUGCUGGAUGGUAUUAAUCUtg-3′ (SEQ ID NO: 2363)3′-AGGACUACGACCUACCAUAAUUAGAAC-5′ (SEQ ID NO: 4377) LDHA-1477 Target:5′-TCCTGATGCTGGATGGTATTAATCTTG-3′ (SEQ ID NO: 6391)5′-UGAUGCUGGAUGGUAUUAAUCUUgt-3′ (SEQ ID NO: 2364)3′-GGACUACGACCUACCAUAAUUAGAACA-5′ (SEQ ID NO: 4378) LDHA-1478 Target:5′-CCTGATGCTGGATGGTATTAATCTTGT-3′ (SEQ ID NO: 6392)5′-GAUGCUGGAUGGUAUUAAUCUUGtg-3′ (SEQ ID NO: 2365)3′-GACUACGACCUACCAUAAUUAGAACAC-5′ (SEQ ID NO: 4379) LDHA-1479 Target:5′-CTGATGCTGGATGGTATTAATCTTGTG-3′ (SEQ ID NO: 6393)5′-AUGCUGGAUGGUAUUAAUCUUGUgt-3′ (SEQ ID NO: 2366)3′-ACUACGACCUACCAUAAUUAGAACACA-5′ (SEQ ID NO: 4380) LDHA-1480 Target:5′-TGATGCTGGATGGTATTAATCTTGTGT-3′ (SEQ ID NO: 6394)5′-UGCUGGAUGGUAUUAAUCUUGUGta-3′ (SEQ ID NO: 2367)3′-CUACGACCUACCAUAAUUAGAACACAU-5′ (SEQ ID NO: 4381) LDHA-1481 Target:5′-GATGCTGGATGGTATTAATCTTGTGTA-3′ (SEQ ID NO: 6395)5′-GCUGGAUGGUAUUAAUCUUGUGUag-3′ (SEQ ID NO: 2368)3′-UACGACCUACCAUAAUUAGAACACAUC-5′ (SEQ ID NO: 4382) LDHA-1482 Target:5′-ATGCTGGATGGTATTAATCTTGTGTAG-3′ (SEQ ID NO: 6396)5′-CUGGAUGGUAUUAAUCUUGUGUAgt-3′ (SEQ ID NO: 2369)3′-ACGACCUACCAUAAUUAGAACACAUCA-5′ (SEQ ID NO: 4383) LDHA-1483 Target:5′-TGCTGGATGGTATTAATCTTGTGTAGT-3′ (SEQ ID NO: 6397)5′-UGGAUGGUAUUAAUCUUGUGUAGtc-3′ (SEQ ID NO: 2370)3′-CGACCUACCAUAAUUAGAACACAUCAG-5′ (SEQ ID NO: 4384) LDHA-1484 Target:5′-GCTGGATGGTATTAATCTTGTGTAGTC-3′ (SEQ ID NO: 6398)5′-GGAUGGUAUUAAUCUUGUGUAGUct-3′ (SEQ ID NO: 2371)3′-GACCUACCAUAAUUAGAACACAUCAGA-5′ (SEQ ID NO: 4385) LDHA-1485 Target:5′-CTGGATGGTATTAATCTTGTGTAGTCT-3′ (SEQ ID NO: 6399)5′-GAUGGUAUUAAUCUUGUGUAGUCtt-3′ (SEQ ID NO: 2372)3′-ACCUACCAUAAUUAGAACACAUCAGAA-5′ (SEQ ID NO: 4386) LDHA-1486 Target:5′-TGGATGGTATTAATCTTGTGTAGTCTT-3′ (SEQ ID NO: 6400)5′-AUGGUAUUAAUCUUGUGUAGUCUtc-3′ (SEQ ID NO: 2373)3′-CCUACCAUAAUUAGAACACAUCAGAAG-5′ (SEQ ID NO: 4387) LDHA-1487 Target:5′-GGATGGTATTAATCTTGTGTAGTCTTC-3′ (SEQ ID NO: 6401)5′-UGGUAUUAAUCUUGUGUAGUCUUca-3′ (SEQ ID NO: 2374)3′-CUACCAUAAUUAGAACACAUCAGAAGU-5′ (SEQ ID NO: 4388) LDHA-1488 Target:5′-GATGGTATTAATCTTGTGTAGTCTTCA-3′ (SEQ ID NO: 6402)5′-GGUAUUAAUCUUGUGUAGUCUUCaa-3′ (SEQ ID NO: 2375)3′-UACCAUAAUUAGAACACAUCAGAAGUU-5′ (SEQ ID NO: 4389) LDHA-1489 Target:5′-ATGGTATTAATCTTGTGTAGTCTTCAA-3′ (SEQ ID NO: 6403)5′-GUAUUAAUCUUGUGUAGUCUUCAac-3′ (SEQ ID NO: 2376)3′-ACCAUAAUUAGAACACAUCAGAAGUUG-5′ (SEQ ID NO: 4390) LDHA-1490 Target:5′-TGGTATTAATCTTGTGTAGTCTTCAAC-3′ (SEQ ID NO: 6404)5′-UAUUAAUCUUGUGUAGUCUUCAAct-3′ (SEQ ID NO: 2377)3′-CCAUAAUUAGAACACAUCAGAAGUUGA-5′ (SEQ ID NO: 4391) LDHA-1491 Target:5′-GGTATTAATCTTGTGTAGTCTTCAACT-3′ (SEQ ID NO: 6405)5′-AUUAAUCUUGUGUAGUCUUCAACtg-3′ (SEQ ID NO: 2378)3′-CAUAAUUAGAACACAUCAGAAGUUGAC-5′ (SEQ ID NO: 4392) LDHA-1492 Target:5′-GTATTAATCTTGTGTAGTCTTCAACTG-3′ (SEQ ID NO: 6406)5′-UUAAUCUUGUGUAGUCUUCAACUgg-3′ (SEQ ID NO: 2379)3′-AUAAUUAGAACACAUCAGAAGUUGACC-5′ (SEQ ID NO: 4393) LDHA-1493 Target:5′-TATTAATCTTGTGTAGTCTTCAACTGG-3′ (SEQ ID NO: 6407)5′-UAAUCUUGUGUAGUCUUCAACUGgt-3′ (SEQ ID NO: 2380)3′-UAAUUAGAACACAUCAGAAGUUGACCA-5′ (SEQ ID NO: 4394) LDHA-1494 Target:5′-ATTAATCTTGTGTAGTCTTCAACTGGT-3′ (SEQ ID NO: 6408)5′-AAUCUUGUGUAGUCUUCAACUGGtt-3′ (SEQ ID NO: 2381)3′-AAUUAGAACACAUCAGAAGUUGACCAA-5′ (SEQ ID NO: 4395) LDHA-1495 Target:5′-TTAATCTTGTGTAGTCTTCAACTGGTT-3′ (SEQ ID NO: 6409)5′-AUCUUGUGUAGUCUUCAACUGGUta-3′ (SEQ ID NO: 2382)3′-AUUAGAACACAUCAGAAGUUGACCAAU-5′ (SEQ ID NO: 4396) LDHA-1496 Target:5′-TAATCTTGTGTAGTCTTCAACTGGTTA-3′ (SEQ ID NO: 6410)5′-UCUUGUGUAGUCUUCAACUGGUUag-3′ (SEQ ID NO: 2383)3′-UUAGAACACAUCAGAAGUUGACCAAUC-5′ (SEQ ID NO: 4397) LDHA-1497 Target:5′-AATCTTGTGTAGTCTTCAACTGGTTAG-3′ (SEQ ID NO: 6411)5′-CUUGUGUAGUCUUCAACUGGUUAgt-3′ (SEQ ID NO: 2384)3′-UAGAACACAUCAGAAGUUGACCAAUCA-5′ (SEQ ID NO: 4398) LDHA-1498 Target:5′-ATCTTGTGTAGTCTTCAACTGGTTAGT-3′ (SEQ ID NO: 6412)5′-UUGUGUAGUCUUCAACUGGUUAGtg-3′ (SEQ ID NO: 2385)3′-AGAACACAUCAGAAGUUGACCAAUCAC-5′ (SEQ ID NO: 4399) LDHA-1499 Target:5′-TCTTGTGTAGTCTTCAACTGGTTAGTG-3′ (SEQ ID NO: 6413)5′-UGUGUAGUCUUCAACUGGUUAGUgt-3′ (SEQ ID NO: 2386)3′-GAACACAUCAGAAGUUGACCAAUCACA-5′ (SEQ ID NO: 4400) LDHA-1500 Target:5′-CTTGTGTAGTCTTCAACTGGTTAGTGT-3′ (SEQ ID NO: 6414)5′-GUGUAGUCUUCAACUGGUUAGUGtg-3′ (SEQ ID NO: 2387)3′-AACACAUCAGAAGUUGACCAAUCACAC-5′ (SEQ ID NO: 4401) LDHA-1501 Target:5′-TTGTGTAGTCTTCAACTGGTTAGTGTG-3′ (SEQ ID NO: 6415)5′-UGUAGUCUUCAACUGGUUAGUGUga-3′ (SEQ ID NO: 2388)3′-ACACAUCAGAAGUUGACCAAUCACACU-5′ (SEQ ID NO: 4402) LDHA-1502 Target:5′-TGTGTAGTCTTCAACTGGTTAGTGTGA-3′ (SEQ ID NO: 6416)5′-GUAGUCUUCAACUGGUUAGUGUGaa-3′ (SEQ ID NO: 2389)3′-CACAUCAGAAGUUGACCAAUCACACUU-5′ (SEQ ID NO: 4403) LDHA-1503 Target:5′-GTGTAGTCTTCAACTGGTTAGTGTGAA-3′ (SEQ ID NO: 6417)5′-UAGUCUUCAACUGGUUAGUGUGAaa-3′ (SEQ ID NO: 2390)3′-ACAUCAGAAGUUGACCAAUCACACUUU-5′ (SEQ ID NO: 4404) LDHA-1504 Target:5′-TGTAGTCTTCAACTGGTTAGTGTGAAA-3′ (SEQ ID NO: 6418)5′-AGUCUUCAACUGGUUAGUGUGAAat-3′ (SEQ ID NO: 2391)3′-CAUCAGAAGUUGACCAAUCACACUUUA-5′ (SEQ ID NO: 4405) LDHA-1505 Target:5′-GTAGTCTTCAACTGGTTAGTGTGAAAT-3′ (SEQ ID NO: 6419)5′-GUCUUCAACUGGUUAGUGUGAAAta-3′ (SEQ ID NO: 2392)3′-AUCAGAAGUUGACCAAUCACACUUUAU-5′ (SEQ ID NO: 4406) LDHA-1506 Target:5′-TAGTCTTCAACTGGTTAGTGTGAAATA-3′ (SEQ ID NO: 6420)5′-UCUUCAACUGGUUAGUGUGAAAUag-3′ (SEQ ID NO: 2393)3′-UCAGAAGUUGACCAAUCACACUUUAUC-5′ (SEQ ID NO: 4407) LDHA-1507 Target:5′-AGTCTTCAACTGGTTAGTGTGAAATAG-3′ (SEQ ID NO: 6421)5′-CUUCAACUGGUUAGUGUGAAAUAgt-3′ (SEQ ID NO: 2394)3′-CAGAAGUUGACCAAUCACACUUUAUCA-5′ (SEQ ID NO: 4408) LDHA-1508 Target:5′-GTCTTCAACTGGTTAGTGTGAAATAGT-3′ (SEQ ID NO: 6422)5′-UUCAACUGGUUAGUGUGAAAUAGtt-3′ (SEQ ID NO: 2395)3′-AGAAGUUGACCAAUCACACUUUAUCAA-5′ (SEQ ID NO: 4409) LDHA-1509 Target:5′-TCTTCAACTGGTTAGTGTGAAATAGTT-3′ (SEQ ID NO: 6423)5′-UCAACUGGUUAGUGUGAAAUAGUtc-3′ (SEQ ID NO: 2396)3′-GAAGUUGACCAAUCACACUUUAUCAAG-5′ (SEQ ID NO: 4410) LDHA-1510 Target:5′-CTTCAACTGGTTAGTGTGAAATAGTTC-3′ (SEQ ID NO: 6424)5′-CAACUGGUUAGUGUGAAAUAGUUct-3′ (SEQ ID NO: 2397)3′-AAGUUGACCAAUCACACUUUAUCAAGA-5′ (SEQ ID NO: 4411) LDHA-1511 Target:5′-TTCAACTGGTTAGTGTGAAATAGTTCT-3′ (SEQ ID NO: 6425)5′-UGGUUAGUGUGAAAUAGUUCUGCca-3′ (SEQ ID NO: 2398)3′-UGACCAAUCACACUUUAUCAAGACGGU-5′ (SEQ ID NO: 4412) LDHA-1515 Target:5′-ACTGGTTAGTGTGAAATAGTTCTGCCA-3′ (SEQ ID NO: 6426)5′-GUUAGUGUGAAAUAGUUCUGCCAcc-3′ (SEQ ID NO: 2399)3′-ACCAAUCACACUUUAUCAAGACGGUGG-5′ (SEQ ID NO: 4413) LDHA-1517 Target:5′-TGGTTAGTGTGAAATAGTTCTGCCACC-3′ (SEQ ID NO: 6427)5′-UUAGUGUGAAAUAGUUCUGCCACct-3′ (SEQ ID NO: 2400)3′-CCAAUCACACUUUAUCAAGACGGUGGA-5′ (SEQ ID NO: 4414) LDHA-1518 Target:5′-GGTTAGTGTGAAATAGTTCTGCCACCT-3′ (SEQ ID NO: 6428)5′-UAGUGUGAAAUAGUUCUGCCACCtc-3′ (SEQ ID NO: 2401)3′-CAAUCACACUUUAUCAAGACGGUGGAG-5′ (SEQ ID NO: 4415) LDHA-1519 Target:5′-GTTAGTGTGAAATAGTTCTGCCACCTC-3′ (SEQ ID NO: 6429)5′-AGUGUGAAAUAGUUCUGCCACCUct-3′ (SEQ ID NO: 2402)3′-AAUCACACUUUAUCAAGACGGUGGAGA-5′ (SEQ ID NO: 4416) LDHA-1520 Target:5′-TTAGTGTGAAATAGTTCTGCCACCTCT-3′ (SEQ ID NO: 6430)5′-GUGUGAAAUAGUUCUGCCACCUCtg-3′ (SEQ ID NO: 2403)3′-AUCACACUUUAUCAAGACGGUGGAGAC-5′ (SEQ ID NO: 4417) LDHA-1521 Target:5′-TAGTGTGAAATAGTTCTGCCACCTCTG-3′ (SEQ ID NO: 6431)5′-UGUGAAAUAGUUCUGCCACCUCUga-3′ (SEQ ID NO: 2404)3′-UCACACUUUAUCAAGACGGUGGAGACU-5′ (SEQ ID NO: 4418) LDHA-1522 Target:5′-AGTGTGAAATAGTTCTGCCACCTCTGA-3′ (SEQ ID NO: 6432)5′-GUGAAAUAGUUCUGCCACCUCUGac-3′ (SEQ ID NO: 2405)3′-CACACUUUAUCAAGACGGUGGAGACUG-5′ (SEQ ID NO: 4419) LDHA-1523 Target:5′-GTGTGAAATAGTTCTGCCACCTCTGAC-3′ (SEQ ID NO: 6433)5′-UGAAAUAGUUCUGCCACCUCUGAcg-3′ (SEQ ID NO: 2406)3′-ACACUUUAUCAAGACGGUGGAGACUGC-5′ (SEQ ID NO: 4420) LDHA-1524 Target:5′-TGTGAAATAGTTCTGCCACCTCTGACG-3′ (SEQ ID NO: 6434)5′-GAAAUAGUUCUGCCACCUCUGACgc-3′ (SEQ ID NO: 2407)3′-CACUUUAUCAAGACGGUGGAGACUGCG-5′ (SEQ ID NO: 4421) LDHA-1525 Target:5′-GTGAAATAGTTCTGCCACCTCTGACGC-3′ (SEQ ID NO: 6435)5′-AAAUAGUUCUGCCACCUCUGACGca-3′ (SEQ ID NO: 2408)3′-ACUUUAUCAAGACGGUGGAGACUGCGU-5′ (SEQ ID NO: 4422) LDHA-1526 Target:5′-TGAAATAGTTCTGCCACCTCTGACGCA-3′ (SEQ ID NO: 6436)5′-AAUAGUUCUGCCACCUCUGACGCac-3′ (SEQ ID NO: 2409)3′-CUUUAUCAAGACGGUGGAGACUGCGUG-5′ (SEQ ID NO: 4423) LDHA-1527 Target:5′-GAAATAGTTCTGCCACCTCTGACGCAC-3′ (SEQ ID NO: 6437)5′-AUAGUUCUGCCACCUCUGACGCAcc-3′ (SEQ ID NO: 2410)3′-UUUAUCAAGACGGUGGAGACUGCGUGG-5′ (SEQ ID NO: 4424) LDHA-1528 Target:5′-AAATAGTTCTGCCACCTCTGACGCACC-3′ (SEQ ID NO: 6438)5′-UAGUUCUGCCACCUCUGACGCACca-3′ (SEQ ID NO: 2411)3′-UUAUCAAGACGGUGGAGACUGCGUGGU-5′ (SEQ ID NO: 4425) LDHA-1529 Target:5′-AATAGTTCTGCCACCTCTGACGCACCA-3′ (SEQ ID NO: 6439)5′-AGUUCUGCCACCUCUGACGCACCac-3′ (SEQ ID NO: 2412)3′-UAUCAAGACGGUGGAGACUGCGUGGUG-5′ (SEQ ID NO: 4426) LDHA-1530 Target:5′-ATAGTTCTGCCACCTCTGACGCACCAC-3′ (SEQ ID NO: 6440)5′-GUUCUGCCACCUCUGACGCACCAct-3′ (SEQ ID NO: 2413)3′-AUCAAGACGGUGGAGACUGCGUGGUGA-5′ (SEQ ID NO: 4427) LDHA-1531 Target:5′-TAGTTCTGCCACCTCTGACGCACCACT-3′ (SEQ ID NO: 6441)5′-UUCUGCCACCUCUGACGCACCACtg-3′ (SEQ ID NO: 2414)3′-UCAAGACGGUGGAGACUGCGUGGUGAC-5′ (SEQ ID NO: 4428) LDHA-1532 Target:5′-AGTTCTGCCACCTCTGACGCACCACTG-3′ (SEQ ID NO: 6442)5′-UCUGCCACCUCUGACGCACCACUgc-3′ (SEQ ID NO: 2415)3′-CAAGACGGUGGAGACUGCGUGGUGACG-5′ (SEQ ID NO: 4429) LDHA-1533 Target:5′-GTTCTGCCACCTCTGACGCACCACTGC-3′ (SEQ ID NO: 6443)5′-CUGCCACCUCUGACGCACCACUGcc-3′ (SEQ ID NO: 2416)3′-AAGACGGUGGAGACUGCGUGGUGACGG-5′ (SEQ ID NO: 4430) LDHA-1534 Target:5′-TTCTGCCACCTCTGACGCACCACTGCC-3′ (SEQ ID NO: 6444)5′-UGCCACCUCUGACGCACCACUGCca-3′ (SEQ ID NO: 2417)3′-AGACGGUGGAGACUGCGUGGUGACGGU-5′ (SEQ ID NO: 4431) LDHA-1535 Target:5′-TCTGCCACCTCTGACGCACCACTGCCA-3′ (SEQ ID NO: 6445)5′-GCCACCUCUGACGCACCACUGCCaa-3′ (SEQ ID NO: 2418)3′-GACGGUGGAGACUGCGUGGUGACGGUU-5′ (SEQ ID NO: 4432) LDHA-1536 Target:5′-CTGCCACCTCTGACGCACCACTGCCAA-3′ (SEQ ID NO: 6446)5′-CCACCUCUGACGCACCACUGCCAat-3′ (SEQ ID NO: 2419)3′-ACGGUGGAGACUGCGUGGUGACGGUUA-5′ (SEQ ID NO: 4433) LDHA-1537 Target:5′-TGCCACCTCTGACGCACCACTGCCAAT-3′ (SEQ ID NO: 6447)5′-CACCUCUGACGCACCACUGCCAAtg-3′ (SEQ ID NO: 2420)3′-CGGUGGAGACUGCGUGGUGACGGUUAC-5′ (SEQ ID NO: 4434) LDHA-1538 Target:5′-GCCACCTCTGACGCACCACTGCCAATG-3′ (SEQ ID NO: 6448)5′-ACCUCUGACGCACCACUGCCAAUgc-3′ (SEQ ID NO: 2421)3′-GGUGGAGACUGCGUGGUGACGGUUACG-5′ (SEQ ID NO: 4435) LDHA-1539 Target:5′-CCACCTCTGACGCACCACTGCCAATGC-3′ (SEQ ID NO: 6449)5′-CCUCUGACGCACCACUGCCAAUGct-3′ (SEQ ID NO: 2422)3′-GUGGAGACUGCGUGGUGACGGUUACGA-5′ (SEQ ID NO: 4436) LDHA-1540 Target:5′-CACCTCTGACGCACCACTGCCAATGCT-3′ (SEQ ID NO: 6450)5′-CUCUGACGCACCACUGCCAAUGCtg-3′ (SEQ ID NO: 2423)3′-UGGAGACUGCGUGGUGACGGUUACGAC-5′ (SEQ ID NO: 4437) LDHA-1541 Target:5′-ACCTCTGACGCACCACTGCCAATGCTG-3′ (SEQ ID NO: 6451)5′-UCUGACGCACCACUGCCAAUGCUgt-3′ (SEQ ID NO: 2424)3′-GGAGACUGCGUGGUGACGGUUACGACA-5′ (SEQ ID NO: 4438) LDHA-1542 Target:5′-CCTCTGACGCACCACTGCCAATGCTGT-3′ (SEQ ID NO: 6452)5′-CUGACGCACCACUGCCAAUGCUGta-3′ (SEQ ID NO: 2425)3′-GAGACUGCGUGGUGACGGUUACGACAU-5′ (SEQ ID NO: 4439) LDHA-1543 Target:5′-CTCTGACGCACCACTGCCAATGCTGTA-3′ (SEQ ID NO: 6453)5′-UGACGCACCACUGCCAAUGCUGUac-3′ (SEQ ID NO: 2426)3′-AGACUGCGUGGUGACGGUUACGACAUG-5′ (SEQ ID NO: 4440) LDHA-1544 Target:5′-TCTGACGCACCACTGCCAATGCTGTAC-3′ (SEQ ID NO: 6454)5′-GACGCACCACUGCCAAUGCUGUAcg-3′ (SEQ ID NO: 2427)3′-GACUGCGUGGUGACGGUUACGACAUGC-5′ (SEQ ID NO: 4441) LDHA-1545 Target:5′-CTGACGCACCACTGCCAATGCTGTACG-3′ (SEQ ID NO: 6455)5′-ACGCACCACUGCCAAUGCUGUACgt-3′ (SEQ ID NO: 2428)3′-ACUGCGUGGUGACGGUUACGACAUGCA-5′ (SEQ ID NO: 4442) LDHA-1546 Target:5′-TGACGCACCACTGCCAATGCTGTACGT-3′ (SEQ ID NO: 6456)5′-CGCACCACUGCCAAUGCUGUACGta-3′ (SEQ ID NO: 2429)3′-CUGCGUGGUGACGGUUACGACAUGCAU-5′ (SEQ ID NO: 4443) LDHA-1547 Target:5′-GACGCACCACTGCCAATGCTGTACGTA-3′ (SEQ ID NO: 6457)5′-GCACCACUGCCAAUGCUGUACGUac-3′ (SEQ ID NO: 2430)3′-UGCGUGGUGACGGUUACGACAUGCAUG-5′ (SEQ ID NO: 4444) LDHA-1548 Target:5′-ACGCACCACTGCCAATGCTGTACGTAC-3′ (SEQ ID NO: 6458)5′-CACCACUGCCAAUGCUGUACGUAct-3′ (SEQ ID NO: 2431)3′-GCGUGGUGACGGUUACGACAUGCAUGA-5′ (SEQ ID NO: 4445) LDHA-1549 Target:5′-CGCACCACTGCCAATGCTGTACGTACT-3′ (SEQ ID NO: 6459)5′-ACCACUGCCAAUGCUGUACGUACtg-3′ (SEQ ID NO: 2432)3′-CGUGGUGACGGUUACGACAUGCAUGAC-5′ (SEQ ID NO: 4446) LDHA-1550 Target:5′-GCACCACTGCCAATGCTGTACGTACTG-3′ (SEQ ID NO: 6460)5′-CCACUGCCAAUGCUGUACGUACUgc-3′ (SEQ ID NO: 2433)3′-GUGGUGACGGUUACGACAUGCAUGACG-5′ (SEQ ID NO: 4447) LDHA-1551 Target:5′-CACCACTGCCAATGCTGTACGTACTGC-3′ (SEQ ID NO: 6461)5′-CACUGCCAAUGCUGUACGUACUGca-3′ (SEQ ID NO: 2434)3′-UGGUGACGGUUACGACAUGCAUGACGU-5′ (SEQ ID NO: 4448) LDHA-1552 Target:5′-ACCACTGCCAATGCTGTACGTACTGCA-3′ (SEQ ID NO: 6462)5′-ACUGCCAAUGCUGUACGUACUGCat-3′ (SEQ ID NO: 2435)3′-GGUGACGGUUACGACAUGCAUGACGUA-5′ (SEQ ID NO: 4449) LDHA-1553 Target:5′-CCACTGCCAATGCTGTACGTACTGCAT-3′ (SEQ ID NO: 6463)5′-CUGCCAAUGCUGUACGUACUGCAtt-3′ (SEQ ID NO: 2436)3′-GUGACGGUUACGACAUGCAUGACGUAA-5′ (SEQ ID NO: 4450) LDHA-1554 Target:5′-CACTGCCAATGCTGTACGTACTGCATT-3′ (SEQ ID NO: 6464)5′-UGCCAAUGCUGUACGUACUGCAUtt-3′ (SEQ ID NO: 2437)3′-UGACGGUUACGACAUGCAUGACGUAAA-5′ (SEQ ID NO: 4451) LDHA-1555 Target:5′-ACTGCCAATGCTGTACGTACTGCATTT-3′ (SEQ ID NO: 6465)5′-GCCAAUGCUGUACGUACUGCAUUtg-3′ (SEQ ID NO: 2438)3′-GACGGUUACGACAUGCAUGACGUAAAC-5′ (SEQ ID NO: 4452) LDHA-1556 Target:5′-CTGCCAATGCTGTACGTACTGCATTTG-3′ (SEQ ID NO: 6466)5′-CCAAUGCUGUACGUACUGCAUUUgc-3′ (SEQ ID NO: 2439)3′-ACGGUUACGACAUGCAUGACGUAAACG-5′ (SEQ ID NO: 4453) LDHA-1557 Target:5′-TGCCAATGCTGTACGTACTGCATTTGC-3′ (SEQ ID NO: 6467)5′-CAAUGCUGUACGUACUGCAUUUGcc-3′ (SEQ ID NO: 2440)3′-CGGUUACGACAUGCAUGACGUAAACGG-5′ (SEQ ID NO: 4454) LDHA-1558 Target:5′-GCCAATGCTGTACGTACTGCATTTGCC-3′ (SEQ ID NO: 6468)5′-AAUGCUGUACGUACUGCAUUUGCcc-3′ (SEQ ID NO: 2441)3′-GGUUACGACAUGCAUGACGUAAACGGG-5′ (SEQ ID NO: 4455) LDHA-1559 Target:5′-CCAATGCTGTACGTACTGCATTTGCCC-3′ (SEQ ID NO: 6469)5′-AUGCUGUACGUACUGCAUUUGCCcc-3′ (SEQ ID NO: 2442)3′-GUUACGACAUGCAUGACGUAAACGGGG-5′ (SEQ ID NO: 4456) LDHA-1560 Target:5′-CAATGCTGTACGTACTGCATTTGCCCC-3′ (SEQ ID NO: 6470)5′-UGCUGUACGUACUGCAUUUGCCCct-3′ (SEQ ID NO: 2443)3′-UUACGACAUGCAUGACGUAAACGGGGA-5′ (SEQ ID NO: 4457) LDHA-1561 Target:5′-AATGCTGTACGTACTGCATTTGCCCCT-3′ (SEQ ID NO: 6471)5′-GCUGUACGUACUGCAUUUGCCCCtt-3′ (SEQ ID NO: 2444)3′-UACGACAUGCAUGACGUAAACGGGGAA-5′ (SEQ ID NO: 4458) LDHA-1562 Target:5′-ATGCTGTACGTACTGCATTTGCCCCTT-3′ (SEQ ID NO: 6472)5′-CUGUACGUACUGCAUUUGCCCCUtg-3′ (SEQ ID NO: 2445)3′-ACGACAUGCAUGACGUAAACGGGGAAC-5′ (SEQ ID NO: 4459) LDHA-1563 Target:5′-TGCTGTACGTACTGCATTTGCCCCTTG-3′ (SEQ ID NO: 6473)5′-UGUACGUACUGCAUUUGCCCCUUga-3′ (SEQ ID NO: 2446)3′-CGACAUGCAUGACGUAAACGGGGAACU-5′ (SEQ ID NO: 4460) LDHA-1564 Target:5′-GCTGTACGTACTGCATTTGCCCCTTGA-3′ (SEQ ID NO: 6474)5′-GUACGUACUGCAUUUGCCCCUUGag-3′ (SEQ ID NO: 2447)3′-GACAUGCAUGACGUAAACGGGGAACUC-5′ (SEQ ID NO: 4461) LDHA-1565 Target:5′-CTGTACGTACTGCATTTGCCCCTTGAG-3′ (SEQ ID NO: 6475)5′-UACGUACUGCAUUUGCCCCUUGAgc-3′ (SEQ ID NO: 2448)3′-ACAUGCAUGACGUAAACGGGGAACUCG-5′ (SEQ ID NO: 4462) LDHA-1566 Target:5′-TGTACGTACTGCATTTGCCCCTTGAGC-3′ (SEQ ID NO: 6476)5′-ACGUACUGCAUUUGCCCCUUGAGcc-3′ (SEQ ID NO: 2449)3′-CAUGCAUGACGUAAACGGGGAACUCGG-5′ (SEQ ID NO: 4463) LDHA-1567 Target:5′-GTACGTACTGCATTTGCCCCTTGAGCC-3′ (SEQ ID NO: 6477)5′-CGUACUGCAUUUGCCCCUUGAGCca-3′ (SEQ ID NO: 2450)3′-AUGCAUGACGUAAACGGGGAACUCGGU-5′ (SEQ ID NO: 4464) LDHA-1568 Target:5′-TACGTACTGCATTTGCCCCTTGAGCCA-3′ (SEQ ID NO: 6478)5′-GUACUGCAUUUGCCCCUUGAGCCag-3′ (SEQ ID NO: 2451)3′-UGCAUGACGUAAACGGGGAACUCGGUC-5′ (SEQ ID NO: 4465) LDHA-1569 Target:5′-ACGTACTGCATTTGCCCCTTGAGCCAG-3′ (SEQ ID NO: 6479)5′-UACUGCAUUUGCCCCUUGAGCCAgg-3′ (SEQ ID NO: 2452)3′-GCAUGACGUAAACGGGGAACUCGGUCC-5′ (SEQ ID NO: 4466) LDHA-1570 Target:5′-CGTACTGCATTTGCCCCTTGAGCCAGG-3′ (SEQ ID NO: 6480)5′-ACUGCAUUUGCCCCUUGAGCCAGgt-3′ (SEQ ID NO: 2453)3′-CAUGACGUAAACGGGGAACUCGGUCCA-5′ (SEQ ID NO: 4467) LDHA-1571 Target:5′-GTACTGCATTTGCCCCTTGAGCCAGGT-3′ (SEQ ID NO: 6481)5′-CUGCAUUUGCCCCUUGAGCCAGGtg-3′ (SEQ ID NO: 2454)3′-AUGACGUAAACGGGGAACUCGGUCCAC-5′ (SEQ ID NO: 4468) LDHA-1572 Target:5′-TACTGCATTTGCCCCTTGAGCCAGGTG-3′ (SEQ ID NO: 6482)5′-UGCAUUUGCCCCUUGAGCCAGGUgg-3′ (SEQ ID NO: 2455)3′-UGACGUAAACGGGGAACUCGGUCCACC-5′ (SEQ ID NO: 4469) LDHA-1573 Target:5′-ACTGCATTTGCCCCTTGAGCCAGGTGG-3′ (SEQ ID NO: 6483)5′-GCAUUUGCCCCUUGAGCCAGGUGga-3′ (SEQ ID NO: 2456)3′-GACGUAAACGGGGAACUCGGUCCACCU-5′ (SEQ ID NO: 4470) LDHA-1574 Target:5′-CTGCATTTGCCCCTTGAGCCAGGTGGA-3′ (SEQ ID NO: 6484)5′-CAUUUGCCCCUUGAGCCAGGUGGat-3′ (SEQ ID NO: 2457)3′-ACGUAAACGGGGAACUCGGUCCACCUA-5′ (SEQ ID NO: 4471) LDHA-1575 Target:5′-TGCATTTGCCCCTTGAGCCAGGTGGAT-3′ (SEQ ID NO: 6485)5′-AUUUGCCCCUUGAGCCAGGUGGAtg-3′ (SEQ ID NO: 2458)3′-CGUAAACGGGGAACUCGGUCCACCUAC-5′ (SEQ ID NO: 4472) LDHA-1576 Target:5′-GCATTTGCCCCTTGAGCCAGGTGGATG-3′ (SEQ ID NO: 6486)5′-UUUGCCCCUUGAGCCAGGUGGAUgt-3′ (SEQ ID NO: 2459)3′-GUAAACGGGGAACUCGGUCCACCUACA-5′ (SEQ ID NO: 4473) LDHA-1577 Target:5′-CATTTGCCCCTTGAGCCAGGTGGATGT-3′ (SEQ ID NO: 6487)5′-UUGCCCCUUGAGCCAGGUGGAUGtt-3′ (SEQ ID NO: 2460)3′-UAAACGGGGAACUCGGUCCACCUACAA-5′ (SEQ ID NO: 4474) LDHA-1578 Target:5′-ATTTGCCCCTTGAGCCAGGTGGATGTT-3′ (SEQ ID NO: 6488)5′-UGCCCCUUGAGCCAGGUGGAUGUtt-3′ (SEQ ID NO: 2461)3′-AAACGGGGAACUCGGUCCACCUACAAA-5′ (SEQ ID NO: 4475) LDHA-1579 Target:5′-TTTGCCCCTTGAGCCAGGTGGATGTTT-3′ (SEQ ID NO: 6489)5′-GCCCCUUGAGCCAGGUGGAUGUUta-3′ (SEQ ID NO: 2462)3′-AACGGGGAACUCGGUCCACCUACAAAU-5′ (SEQ ID NO: 4476) LDHA-1580 Target:5′-TTGCCCCTTGAGCCAGGTGGATGTTTA-3′ (SEQ ID NO: 6490)5′-CCCCUUGAGCCAGGUGGAUGUUUac-3′ (SEQ ID NO: 2463)3′-ACGGGGAACUCGGUCCACCUACAAAUG-5′ (SEQ ID NO: 4477) LDHA-1581 Target:5′-TGCCCCTTGAGCCAGGTGGATGTTTAC-3′ (SEQ ID NO: 6491)5′-CCCUUGAGCCAGGUGGAUGUUUAcc-3′ (SEQ ID NO: 2464)3′-CGGGGAACUCGGUCCACCUACAAAUGG-5′ (SEQ ID NO: 4478) LDHA-1582 Target:5′-GCCCCTTGAGCCAGGTGGATGTTTACC-3′ (SEQ ID NO: 6492)5′-CCUUGAGCCAGGUGGAUGUUUACcg-3′ (SEQ ID NO: 2465)3′-GGGGAACUCGGUCCACCUACAAAUGGC-5′ (SEQ ID NO: 4479) LDHA-1583 Target:5′-CCCCTTGAGCCAGGTGGATGTTTACCG-3′ (SEQ ID NO: 6493)5′-CUUGAGCCAGGUGGAUGUUUACCgt-3′ (SEQ ID NO: 2466)3′-GGGAACUCGGUCCACCUACAAAUGGCA-5′ (SEQ ID NO: 4480) LDHA-1584 Target:5′-CCCTTGAGCCAGGTGGATGTTTACCGT-3′ (SEQ ID NO: 6494)5′-UUGAGCCAGGUGGAUGUUUACCGtg-3′ (SEQ ID NO: 2467)3′-GGAACUCGGUCCACCUACAAAUGGCAC-5′ (SEQ ID NO: 4481) LDHA-1585 Target:5′-CCTTGAGCCAGGTGGATGTTTACCGTG-3′ (SEQ ID NO: 6495)5′-UGAGCCAGGUGGAUGUUUACCGUgt-3′ (SEQ ID NO: 2468)3′-GAACUCGGUCCACCUACAAAUGGCACA-5′ (SEQ ID NO: 4482) LDHA-1586 Target:5′-CTTGAGCCAGGTGGATGTTTACCGTGT-3′ (SEQ ID NO: 6496)5′-GAGCCAGGUGGAUGUUUACCGUGtg-3′ (SEQ ID NO: 2469)3′-AACUCGGUCCACCUACAAAUGGCACAC-5′ (SEQ ID NO: 4483) LDHA-1587 Target:5′-TTGAGCCAGGTGGATGTTTACCGTGTG-3′ (SEQ ID NO: 6497)5′-AGCCAGGUGGAUGUUUACCGUGUgt-3′ (SEQ ID NO: 2470)3′-ACUCGGUCCACCUACAAAUGGCACACA-5′ (SEQ ID NO: 4484) LDHA-1588 Target:5′-TGAGCCAGGTGGATGTTTACCGTGTGT-3′ (SEQ ID NO: 6498)5′-GCCAGGUGGAUGUUUACCGUGUGtt-3′ (SEQ ID NO: 2471)3′-CUCGGUCCACCUACAAAUGGCACACAA-5′ (SEQ ID NO: 4485) LDHA-1589 Target:5′-GAGCCAGGTGGATGTTTACCGTGTGTT-3′ (SEQ ID NO: 6499)5′-CCAGGUGGAUGUUUACCGUGUGUta-3′ (SEQ ID NO: 2472)3′-UCGGUCCACCUACAAAUGGCACACAAU-5′ (SEQ ID NO: 4486) LDHA-1590 Target:5′-AGCCAGGTGGATGTTTACCGTGTGTTA-3′ (SEQ ID NO: 6500)5′-CAGGUGGAUGUUUACCGUGUGUUat-3′ (SEQ ID NO: 2473)3′-CGGUCCACCUACAAAUGGCACACAAUA-5′ (SEQ ID NO: 4487) LDHA-1591 Target:5′-GCCAGGTGGATGTTTACCGTGTGTTAT-3′ (SEQ ID NO: 6501)5′-AGGUGGAUGUUUACCGUGUGUUAta-3′ (SEQ ID NO: 2474)3′-GGUCCACCUACAAAUGGCACACAAUAU-5′ (SEQ ID NO: 4488) LDHA-1592 Target:5′-CCAGGTGGATGTTTACCGTGTGTTATA-3′ (SEQ ID NO: 6502)5′-GGUGGAUGUUUACCGUGUGUUAUat-3′ (SEQ ID NO: 2475)3′-GUCCACCUACAAAUGGCACACAAUAUA-5′ (SEQ ID NO: 4489) LDHA-1593 Target:5′-CAGGTGGATGTTTACCGTGTGTTATAT-3′ (SEQ ID NO: 6503)5′-GUGGAUGUUUACCGUGUGUUAUAta-3′ (SEQ ID NO: 2476)3′-UCCACCUACAAAUGGCACACAAUAUAU-5′ (SEQ ID NO: 4490) LDHA-1594 Target:5′-AGGTGGATGTTTACCGTGTGTTATATA-3′ (SEQ ID NO: 6504)5′-UGGAUGUUUACCGUGUGUUAUAUaa-3′ (SEQ ID NO: 2477)3′-CCACCUACAAAUGGCACACAAUAUAUU-5′ (SEQ ID NO: 4491) LDHA-1595 Target:5′-GGTGGATGTTTACCGTGTGTTATATAA-3′ (SEQ ID NO: 6505)5′-GGAUGUUUACCGUGUGUUAUAUAac-3′ (SEQ ID NO: 2478)3′-CACCUACAAAUGGCACACAAUAUAUUG-5′ (SEQ ID NO: 4492) LDHA-1596 Target:5′-GTGGATGTTTACCGTGTGTTATATAAC-3′ (SEQ ID NO: 6506)5′-GAUGUUUACCGUGUGUUAUAUAAct-3′ (SEQ ID NO: 2479)3′-ACCUACAAAUGGCACACAAUAUAUUGA-5′ (SEQ ID NO: 4493) LDHA-1597 Target:5′-TGGATGTTTACCGTGTGTTATATAACT-3′ (SEQ ID NO: 6507)5′-AUGUUUACCGUGUGUUAUAUAACtt-3′ (SEQ ID NO: 2480)3′-CCUACAAAUGGCACACAAUAUAUUGAA-5′ (SEQ ID NO: 4494) LDHA-1598 Target:5′-GGATGTTTACCGTGTGTTATATAACTT-3′ (SEQ ID NO: 6508)5′-UGUUUACCGUGUGUUAUAUAACUtc-3′ (SEQ ID NO: 2481)3′-CUACAAAUGGCACACAAUAUAUUGAAG-5′ (SEQ ID NO: 4495) LDHA-1599 Target:5′-GATGTTTACCGTGTGTTATATAACTTC-3′ (SEQ ID NO: 6509)5′-GUUUACCGUGUGUUAUAUAACUUcc-3′ (SEQ ID NO: 2482)3′-UACAAAUGGCACACAAUAUAUUGAAGG-5′ (SEQ ID NO: 4496) LDHA-1600 Target:5′-ATGTTTACCGTGTGTTATATAACTTCC-3′ (SEQ ID NO: 6510)5′-UUUACCGUGUGUUAUAUAACUUCct-3′ (SEQ ID NO: 2483)3′-ACAAAUGGCACACAAUAUAUUGAAGGA-5′ (SEQ ID NO: 4497) LDHA-1601 Target:5′-TGTTTACCGTGTGTTATATAACTTCCT-3′ (SEQ ID NO: 6511)5′-UUACCGUGUGUUAUAUAACUUCCtg-3′ (SEQ ID NO: 2484)3′-CAAAUGGCACACAAUAUAUUGAAGGAC-5′ (SEQ ID NO: 4498) LDHA-1602 Target:5′-GTTTACCGTGTGTTATATAACTTCCTG-3′ (SEQ ID NO: 6512)5′-UACCGUGUGUUAUAUAACUUCCUgg-3′ (SEQ ID NO: 2485)3′-AAAUGGCACACAAUAUAUUGAAGGACC-5′ (SEQ ID NO: 4499) LDHA-1603 Target:5′-TTTACCGTGTGTTATATAACTTCCTGG-3′ (SEQ ID NO: 6513)5′-ACCGUGUGUUAUAUAACUUCCUGgc-3′ (SEQ ID NO: 2486)3′-AAUGGCACACAAUAUAUUGAAGGACCG-5′ (SEQ ID NO: 4500) LDHA-1604 Target:5′-TTACCGTGTGTTATATAACTTCCTGGC-3′ (SEQ ID NO: 6514)5′-CCGUGUGUUAUAUAACUUCCUGGct-3′ (SEQ ID NO: 2487)3′-AUGGCACACAAUAUAUUGAAGGACCGA-5′ (SEQ ID NO: 4501) LDHA-1605 Target:5′-TACCGTGTGTTATATAACTTCCTGGCT-3′ (SEQ ID NO: 6515)5′-CGUGUGUUAUAUAACUUCCUGGCtc-3′ (SEQ ID NO: 2488)3′-UGGCACACAAUAUAUUGAAGGACCGAG-5′ (SEQ ID NO: 4502) LDHA-1606 Target:5′-ACCGTGTGTTATATAACTTCCTGGCTC-3′ (SEQ ID NO: 6516)5′-GUGUGUUAUAUAACUUCCUGGCUcc-3′ (SEQ ID NO: 2489)3′-GGCACACAAUAUAUUGAAGGACCGAGG-5′ (SEQ ID NO: 4503) LDHA-1607 Target:5′-CCGTGTGTTATATAACTTCCTGGCTCC-3′ (SEQ ID NO: 6517)5′-UGUGUUAUAUAACUUCCUGGCUCct-3′ (SEQ ID NO: 2490)3′-GCACACAAUAUAUUGAAGGACCGAGGA-5′ (SEQ ID NO: 4504) LDHA-1608 Target:5′-CGTGTGTTATATAACTTCCTGGCTCCT-3′ (SEQ ID NO: 6518)5′-GUGUUAUAUAACUUCCUGGCUCCtt-3′ (SEQ ID NO: 2491)3′-CACACAAUAUAUUGAAGGACCGAGGAA-5′ (SEQ ID NO: 4505) LDHA-1609 Target:5′-GTGTGTTATATAACTTCCTGGCTCCTT-3′ (SEQ ID NO: 6519)5′-UGUUAUAUAACUUCCUGGCUCCUtc-3′ (SEQ ID NO: 2492)3′-ACACAAUAUAUUGAAGGACCGAGGAAG-5′ (SEQ ID NO: 4506) LDHA-1610 Target:5′-TGTGTTATATAACTTCCTGGCTCCTTC-3′ (SEQ ID NO: 6520)5′-GUUAUAUAACUUCCUGGCUCCUUca-3′ (SEQ ID NO: 2493)3′-CACAAUAUAUUGAAGGACCGAGGAAGU-5′ (SEQ ID NO: 4507) LDHA-1611 Target:5′-GTGTTATATAACTTCCTGGCTCCTTCA-3′ (SEQ ID NO: 6521)5′-UUAUAUAACUUCCUGGCUCCUUCac-3′ (SEQ ID NO: 2494)3′-ACAAUAUAUUGAAGGACCGAGGAAGUG-5′ (SEQ ID NO: 4508) LDHA-1612 Target:5′-TGTTATATAACTTCCTGGCTCCTTCAC-3′ (SEQ ID NO: 6522)5′-UAUAUAACUUCCUGGCUCCUUCAct-3′ (SEQ ID NO: 2495)3′-CAAUAUAUUGAAGGACCGAGGAAGUGA-5′ (SEQ ID NO: 4509) LDHA-1613 Target:5′-GTTATATAACTTCCTGGCTCCTTCACT-3′ (SEQ ID NO: 6523)5′-AUAUAACUUCCUGGCUCCUUCACtg-3′ (SEQ ID NO: 2496)3′-AAUAUAUUGAAGGACCGAGGAAGUGAC-5′ (SEQ ID NO: 4510) LDHA-1614 Target:5′-TTATATAACTTCCTGGCTCCTTCACTG-3′ (SEQ ID NO: 6524)5′-UAUAACUUCCUGGCUCCUUCACUga-3′ (SEQ ID NO: 2497)3′-AUAUAUUGAAGGACCGAGGAAGUGACU-5′ (SEQ ID NO: 4511) LDHA-1615 Target:5′-TATATAACTTCCTGGCTCCTTCACTGA-3′ (SEQ ID NO: 6525)5′-AUAACUUCCUGGCUCCUUCACUGaa-3′ (SEQ ID NO: 2498)3′-UAUAUUGAAGGACCGAGGAAGUGACUU-5′ (SEQ ID NO: 4512) LDHA-1616 Target:5′-ATATAACTTCCTGGCTCCTTCACTGAA-3′ (SEQ ID NO: 6526)5′-UAACUUCCUGGCUCCUUCACUGAac-3′ (SEQ ID NO: 2499)3′-AUAUUGAAGGACCGAGGAAGUGACUUG-5′ (SEQ ID NO: 4513) LDHA-1617 Target:5′-TATAACTTCCTGGCTCCTTCACTGAAC-3′ (SEQ ID NO: 6527)5′-AACUUCCUGGCUCCUUCACUGAAca-3′ (SEQ ID NO: 2500)3′-UAUUGAAGGACCGAGGAAGUGACUUGU-5′ (SEQ ID NO: 4514) LDHA-1618 Target:5′-ATAACTTCCTGGCTCCTTCACTGAACA-3′ (SEQ ID NO: 6528)5′-ACUUCCUGGCUCCUUCACUGAACat-3′ (SEQ ID NO: 2501)3′-AUUGAAGGACCGAGGAAGUGACUUGUA-5′ (SEQ ID NO: 4515) LDHA-1619 Target:5′-TAACTTCCTGGCTCCTTCACTGAACAT-3′ (SEQ ID NO: 6529)5′-CUUCCUGGCUCCUUCACUGAACAtg-3′ (SEQ ID NO: 2502)3′-UUGAAGGACCGAGGAAGUGACUUGUAC-5′ (SEQ ID NO: 4516) LDHA-1620 Target:5′-AACTTCCTGGCTCCTTCACTGAACATG-3′ (SEQ ID NO: 6530)5′-UUCCUGGCUCCUUCACUGAACAUgc-3′ (SEQ ID NO: 2503)3′-UGAAGGACCGAGGAAGUGACUUGUACG-5′ (SEQ ID NO: 4517) LDHA-1621 Target:5′-ACTTCCTGGCTCCTTCACTGAACATGC-3′ (SEQ ID NO: 6531)5′-UCCUGGCUCCUUCACUGAACAUGcc-3′ (SEQ ID NO: 2504)3′-GAAGGACCGAGGAAGUGACUUGUACGG-5′ (SEQ ID NO: 4518) LDHA-1622 Target:5′-CTTCCTGGCTCCTTCACTGAACATGCC-3′ (SEQ ID NO: 6532)5′-CCUGGCUCCUUCACUGAACAUGCct-3′ (SEQ ID NO: 2505)3′-AAGGACCGAGGAAGUGACUUGUACGGA-5′ (SEQ ID NO: 4519) LDHA-1623 Target:5′-TTCCTGGCTCCTTCACTGAACATGCCT-3′ (SEQ ID NO: 6533)5′-CUGGCUCCUUCACUGAACAUGCCta-3′ (SEQ ID NO: 2506)3′-AGGACCGAGGAAGUGACUUGUACGGAU-5′ (SEQ ID NO: 4520) LDHA-1624 Target:5′-TCCTGGCTCCTTCACTGAACATGCCTA-3′ (SEQ ID NO: 6534)5′-UGGCUCCUUCACUGAACAUGCCUag-3′ (SEQ ID NO: 2507)3′-GGACCGAGGAAGUGACUUGUACGGAUC-5′ (SEQ ID NO: 4521) LDHA-1625 Target:5′-CCTGGCTCCTTCACTGAACATGCCTAG-3′ (SEQ ID NO: 6535)5′-GGCUCCUUCACUGAACAUGCCUAgt-3′ (SEQ ID NO: 2508)3′-GACCGAGGAAGUGACUUGUACGGAUCA-5′ (SEQ ID NO: 4522) LDHA-1626 Target:5′-CTGGCTCCTTCACTGAACATGCCTAGT-3′ (SEQ ID NO: 6536)5′-GCUCCUUCACUGAACAUGCCUAGtc-3′ (SEQ ID NO: 2509)3′-ACCGAGGAAGUGACUUGUACGGAUCAG-5′ (SEQ ID NO: 4523) LDHA-1627 Target:5′-TGGCTCCTTCACTGAACATGCCTAGTC-3′ (SEQ ID NO: 6537)5′-CUCCUUCACUGAACAUGCCUAGUcc-3′ (SEQ ID NO: 2510)3′-CCGAGGAAGUGACUUGUACGGAUCAGG-5′ (SEQ ID NO: 4524) LDHA-1628 Target:5′-GGCTCCTTCACTGAACATGCCTAGTCC-3′ (SEQ ID NO: 6538)5′-UCCUUCACUGAACAUGCCUAGUCca-3′ (SEQ ID NO: 2511)3′-CGAGGAAGUGACUUGUACGGAUCAGGU-5′ (SEQ ID NO: 4525) LDHA-1629 Target:5′-GCTCCTTCACTGAACATGCCTAGTCCA-3′ (SEQ ID NO: 6539)5′-CCUUCACUGAACAUGCCUAGUCCaa-3′ (SEQ ID NO: 2512)3′-GAGGAAGUGACUUGUACGGAUCAGGUU-5′ (SEQ ID NO: 4526) LDHA-1630 Target:5′-CTCCTTCACTGAACATGCCTAGTCCAA-3′ (SEQ ID NO: 6540)5′-CUUCACUGAACAUGCCUAGUCCAac-3′ (SEQ ID NO: 2513)3′-AGGAAGUGACUUGUACGGAUCAGGUUG-5′ (SEQ ID NO: 4527) LDHA-1631 Target:5′-TCCTTCACTGAACATGCCTAGTCCAAC-3′ (SEQ ID NO: 6541)5′-UUCACUGAACAUGCCUAGUCCAAca-3′ (SEQ ID NO: 2514)3′-GGAAGUGACUUGUACGGAUCAGGUUGU-5′ (SEQ ID NO: 4528) LDHA-1632 Target:5′-CCTTCACTGAACATGCCTAGTCCAACA-3′ (SEQ ID NO: 6542)5′-UCACUGAACAUGCCUAGUCCAACat-3′ (SEQ ID NO: 2515)3′-GAAGUGACUUGUACGGAUCAGGUUGUA-5′ (SEQ ID NO: 4529) LDHA-1633 Target:5′-CTTCACTGAACATGCCTAGTCCAACAT-3′ (SEQ ID NO: 6543)5′-CACUGAACAUGCCUAGUCCAACAtt-3′ (SEQ ID NO: 2516)3′-AAGUGACUUGUACGGAUCAGGUUGUAA-5′ (SEQ ID NO: 4530) LDHA-1634 Target:5′-TTCACTGAACATGCCTAGTCCAACATT-3′ (SEQ ID NO: 6544)5′-ACUGAACAUGCCUAGUCCAACAUtt-3′ (SEQ ID NO: 2517)3′-AGUGACUUGUACGGAUCAGGUUGUAAA-5′ (SEQ ID NO: 4531) LDHA-1635 Target:5′-TCACTGAACATGCCTAGTCCAACATTT-3′ (SEQ ID NO: 6545)5′-CUGAACAUGCCUAGUCCAACAUUtt-3′ (SEQ ID NO: 2518)3′-GUGACUUGUACGGAUCAGGUUGUAAAA-5′ (SEQ ID NO: 4532) LDHA-1636 Target:5′-CACTGAACATGCCTAGTCCAACATTTT-3′ (SEQ ID NO: 6546)5′-UGAACAUGCCUAGUCCAACAUUUtt-3′ (SEQ ID NO: 2519)3′-UGACUUGUACGGAUCAGGUUGUAAAAA-5′ (SEQ ID NO: 4533) LDHA-1637 Target:5′-ACTGAACATGCCTAGTCCAACATTTTT-3′ (SEQ ID NO: 6547)5′-GAACAUGCCUAGUCCAACAUUUUtt-3′ (SEQ ID NO: 2520)3′-GACUUGUACGGAUCAGGUUGUAAAAAA-5′ (SEQ ID NO: 4534) LDHA-1638 Target:5′-CTGAACATGCCTAGTCCAACATTTTTT-3′ (SEQ ID NO: 6548)5′-AACAUGCCUAGUCCAACAUUUUUtc-3′ (SEQ ID NO: 2521)3′-ACUUGUACGGAUCAGGUUGUAAAAAAG-5′ (SEQ ID NO: 4535) LDHA-1639 Target:5′-TGAACATGCCTAGTCCAACATTTTTTC-3′ (SEQ ID NO: 6549)5′-ACAUGCCUAGUCCAACAUUUUUUcc-3′ (SEQ ID NO: 2522)3′-CUUGUACGGAUCAGGUUGUAAAAAAGG-5′ (SEQ ID NO: 4536) LDHA-1640 Target:5′-GAACATGCCTAGTCCAACATTTTTTCC-3′ (SEQ ID NO: 6550)5′-CAUGCCUAGUCCAACAUUUUUUCcc-3′ (SEQ ID NO: 2523)3′-UUGUACGGAUCAGGUUGUAAAAAAGGG-5′ (SEQ ID NO: 4537) LDHA-1641 Target:5′-AACATGCCTAGTCCAACATTTTTTCCC-3′ (SEQ ID NO: 6551)5′-AUGCCUAGUCCAACAUUUUUUCCca-3′ (SEQ ID NO: 2524)3′-UGUACGGAUCAGGUUGUAAAAAAGGGU-5′ (SEQ ID NO: 4538) LDHA-1642 Target:5′-ACATGCCTAGTCCAACATTTTTTCCCA-3′ (SEQ ID NO: 6552)5′-UGCCUAGUCCAACAUUUUUUCCCag-3′ (SEQ ID NO: 2525)3′-GUACGGAUCAGGUUGUAAAAAAGGGUC-5′ (SEQ ID NO: 4539) LDHA-1643 Target:5′-CATGCCTAGTCCAACATTTTTTCCCAG-3′ (SEQ ID NO: 6553)5′-GCCUAGUCCAACAUUUUUUCCCAgt-3′ (SEQ ID NO: 2526)3′-UACGGAUCAGGUUGUAAAAAAGGGUCA-5′ (SEQ ID NO: 4540) LDHA-1644 Target:5′-ATGCCTAGTCCAACATTTTTTCCCAGT-3′ (SEQ ID NO: 6554)5′-CCUAGUCCAACAUUUUUUCCCAGtg-3′ (SEQ ID NO: 2527)3′-ACGGAUCAGGUUGUAAAAAAGGGUCAC-5′ (SEQ ID NO: 4541) LDHA-1645 Target:5′-TGCCTAGTCCAACATTTTTTCCCAGTG-3′ (SEQ ID NO: 6555)5′-CUAGUCCAACAUUUUUUCCCAGUga-3′ (SEQ ID NO: 2528)3′-CGGAUCAGGUUGUAAAAAAGGGUCACU-5′ (SEQ ID NO: 4542) LDHA-1646 Target:5′-GCCTAGTCCAACATTTTTTCCCAGTGA-3′ (SEQ ID NO: 6556)5′-UAGUCCAACAUUUUUUCCCAGUGag-3′ (SEQ ID NO: 2529)3′-GGAUCAGGUUGUAAAAAAGGGUCACUC-5′ (SEQ ID NO: 4543) LDHA-1647 Target:5′-CCTAGTCCAACATTTTTTCCCAGTGAG-3′ (SEQ ID NO: 6557)5′-AGUCCAACAUUUUUUCCCAGUGAgt-3′ (SEQ ID NO: 2530)3′-GAUCAGGUUGUAAAAAAGGGUCACUCA-5′ (SEQ ID NO: 4544) LDHA-1648 Target:5′-CTAGTCCAACATTTTTTCCCAGTGAGT-3′ (SEQ ID NO: 6558)5′-GUCCAACAUUUUUUCCCAGUGAGtc-3′ (SEQ ID NO: 2531)3′-AUCAGGUUGUAAAAAAGGGUCACUCAG-5′ (SEQ ID NO: 4545) LDHA-1649 Target:5′-TAGTCCAACATTTTTTCCCAGTGAGTC-3′ (SEQ ID NO: 6559)5′-UCCAACAUUUUUUCCCAGUGAGUca-3′ (SEQ ID NO: 2532)3′-UCAGGUUGUAAAAAAGGGUCACUCAGU-5′ (SEQ ID NO: 4546) LDHA-1650 Target:5′-AGTCCAACATTTTTTCCCAGTGAGTCA-3′ (SEQ ID NO: 6560)5′-CCAACAUUUUUUCCCAGUGAGUCac-3′ (SEQ ID NO: 2533)3′-CAGGUUGUAAAAAAGGGUCACUCAGUG-5′ (SEQ ID NO: 4547) LDHA-1651 Target:5′-GTCCAACATTTTTTCCCAGTGAGTCAC-3′ (SEQ ID NO: 6561)5′-CAACAUUUUUUCCCAGUGAGUCAca-3′ (SEQ ID NO: 2534)3′-AGGUUGUAAAAAAGGGUCACUCAGUGU-5′ (SEQ ID NO: 4548) LDHA-1652 Target:5′-TCCAACATTTTTTCCCAGTGAGTCACA-3′ (SEQ ID NO: 6562)5′-AACAUUUUUUCCCAGUGAGUCACat-3′ (SEQ ID NO: 2535)3′-GGUUGUAAAAAAGGGUCACUCAGUGUA-5′ (SEQ ID NO: 4549) LDHA-1653 Target:5′-CCAACATTTTTTCCCAGTGAGTCACAT-3′ (SEQ ID NO: 6563)5′-ACAUUUUUUCCCAGUGAGUCACAtc-3′ (SEQ ID NO: 2536)3′-GUUGUAAAAAAGGGUCACUCAGUGUAG-5′ (SEQ ID NO: 4550) LDHA-1654 Target:5′-CAACATTTTTTCCCAGTGAGTCACATC-3′ (SEQ ID NO: 6564)5′-CAUUUUUUCCCAGUGAGUCACAUcc-3′ (SEQ ID NO: 2537)3′-UUGUAAAAAAGGGUCACUCAGUGUAGG-5′ (SEQ ID NO: 4551) LDHA-1655 Target:5′-AACATTTTTTCCCAGTGAGTCACATCC-3′ (SEQ ID NO: 6565)5′-AUUUUUUCCCAGUGAGUCACAUCct-3′ (SEQ ID NO: 2538)3′-UGUAAAAAAGGGUCACUCAGUGUAGGA-5′ (SEQ ID NO: 4552) LDHA-1656 Target:5′-ACATTTTTTCCCAGTGAGTCACATCCT-3′ (SEQ ID NO: 6566)5′-UUUUUUCCCAGUGAGUCACAUCCtg-3′ (SEQ ID NO: 2539)3′-GUAAAAAAGGGUCACUCAGUGUAGGAC-5′ (SEQ ID NO: 4553) LDHA-1657 Target:5′-CATTTTTTCCCAGTGAGTCACATCCTG-3′ (SEQ ID NO: 6567)5′-UUUUUCCCAGUGAGUCACAUCCUgg-3′ (SEQ ID NO: 2540)3′-UAAAAAAGGGUCACUCAGUGUAGGACC-5′ (SEQ ID NO: 4554) LDHA-1658 Target:5′-ATTTTTTCCCAGTGAGTCACATCCTGG-3′ (SEQ ID NO: 6568)5′-UUUUCCCAGUGAGUCACAUCCUGgg-3′ (SEQ ID NO: 2541)3′-AAAAAAGGGUCACUCAGUGUAGGACCC-5′ (SEQ ID NO: 4555) LDHA-1659 Target:5′-TTTTTTCCCAGTGAGTCACATCCTGGG-3′ (SEQ ID NO: 6569)5′-UUUCCCAGUGAGUCACAUCCUGGga-3′ (SEQ ID NO: 2542)3′-AAAAAGGGUCACUCAGUGUAGGACCCU-5′ (SEQ ID NO: 4556) LDHA-1660 Target:5′-TTTTTCCCAGTGAGTCACATCCTGGGA-3′ (SEQ ID NO: 6570)5′-UUCCCAGUGAGUCACAUCCUGGGat-3′ (SEQ ID NO: 2543)3′-AAAAGGGUCACUCAGUGUAGGACCCUA-5′ (SEQ ID NO: 4557) LDHA-1661 Target:5′-TTTTCCCAGTGAGTCACATCCTGGGAT-3′ (SEQ ID NO: 6571)5′-UCCCAGUGAGUCACAUCCUGGGAtc-3′ (SEQ ID NO: 2544)3′-AAAGGGUCACUCAGUGUAGGACCCUAG-5′ (SEQ ID NO: 4558) LDHA-1662 Target:5′-TTTCCCAGTGAGTCACATCCTGGGATC-3′ (SEQ ID NO: 6572)5′-CCCAGUGAGUCACAUCCUGGGAUcc-3′ (SEQ ID NO: 2545)3′-AAGGGUCACUCAGUGUAGGACCCUAGG-5′ (SEQ ID NO: 4559) LDHA-1663 Target:5′-TTCCCAGTGAGTCACATCCTGGGATCC-3′ (SEQ ID NO: 6573)5′-CCAGUGAGUCACAUCCUGGGAUCca-3′ (SEQ ID NO: 2546)3′-AGGGUCACUCAGUGUAGGACCCUAGGU-5′ (SEQ ID NO: 4560) LDHA-1664 Target:5′-TCCCAGTGAGTCACATCCTGGGATCCA-3′ (SEQ ID NO: 6574)5′-CAGUGAGUCACAUCCUGGGAUCCag-3′ (SEQ ID NO: 2547)3′-GGGUCACUCAGUGUAGGACCCUAGGUC-5′ (SEQ ID NO: 4561) LDHA-1665 Target:5′-CCCAGTGAGTCACATCCTGGGATCCAG-3′ (SEQ ID NO: 6575)5′-AGUGAGUCACAUCCUGGGAUCCAgt-3′ (SEQ ID NO: 2548)3′-GGUCACUCAGUGUAGGACCCUAGGUCA-5′ (SEQ ID NO: 4562) LDHA-1666 Target:5′-CCAGTGAGTCACATCCTGGGATCCAGT-3′ (SEQ ID NO: 6576)5′-GUGAGUCACAUCCUGGGAUCCAGtg-3′ (SEQ ID NO: 2549)3′-GUCACUCAGUGUAGGACCCUAGGUCAC-5′ (SEQ ID NO: 4563) LDHA-1667 Target:5′-CAGTGAGTCACATCCTGGGATCCAGTG-3′ (SEQ ID NO: 6577)5′-UGAGUCACAUCCUGGGAUCCAGUgt-3′ (SEQ ID NO: 2550)3′-UCACUCAGUGUAGGACCCUAGGUCACA-5′ (SEQ ID NO: 4564) LDHA-1668 Target:5′-AGTGAGTCACATCCTGGGATCCAGTGT-3′ (SEQ ID NO: 6578)5′-GAGUCACAUCCUGGGAUCCAGUGta-3′ (SEQ ID NO: 2551)3′-CACUCAGUGUAGGACCCUAGGUCACAU-5′ (SEQ ID NO: 4565) LDHA-1669 Target:5′-GTGAGTCACATCCTGGGATCCAGTGTA-3′ (SEQ ID NO: 6579)5′-AGUCACAUCCUGGGAUCCAGUGUat-3′ (SEQ ID NO: 2552)3′-ACUCAGUGUAGGACCCUAGGUCACAUA-5′ (SEQ ID NO: 4566) LDHA-1670 Target:5′-TGAGTCACATCCTGGGATCCAGTGTAT-3′ (SEQ ID NO: 6580)5′-GUCACAUCCUGGGAUCCAGUGUAta-3′ (SEQ ID NO: 2553)3′-CUCAGUGUAGGACCCUAGGUCACAUAU-5′ (SEQ ID NO: 4567) LDHA-1671 Target:5′-GAGTCACATCCTGGGATCCAGTGTATA-3′ (SEQ ID NO: 6581)5′-UCACAUCCUGGGAUCCAGUGUAUaa-3′ (SEQ ID NO: 2554)3′-UCAGUGUAGGACCCUAGGUCACAUAUU-5′ (SEQ ID NO: 4568) LDHA-1672 Target:5′-AGTCACATCCTGGGATCCAGTGTATAA-3′ (SEQ ID NO: 6582)5′-CACAUCCUGGGAUCCAGUGUAUAaa-3′ (SEQ ID NO: 2555)3′-CAGUGUAGGACCCUAGGUCACAUAUUU-5′ (SEQ ID NO: 4569) LDHA-1673 Target:5′-GTCACATCCTGGGATCCAGTGTATAAA-3′ (SEQ ID NO: 6583)5′-ACAUCCUGGGAUCCAGUGUAUAAat-3′ (SEQ ID NO: 2556)3′-AGUGUAGGACCCUAGGUCACAUAUUUA-5′ (SEQ ID NO: 4570) LDHA-1674 Target:5′-TCACATCCTGGGATCCAGTGTATAAAT-3′ (SEQ ID NO: 6584)5′-CAUCCUGGGAUCCAGUGUAUAAAtc-3′ (SEQ ID NO: 2557)3′-GUGUAGGACCCUAGGUCACAUAUUUAG-5′ (SEQ ID NO: 4571) LDHA-1675 Target:5′-CACATCCTGGGATCCAGTGTATAAATC-3′ (SEQ ID NO: 6585)5′-AUCCUGGGAUCCAGUGUAUAAAUcc-3′ (SEQ ID NO: 2558)3′-UGUAGGACCCUAGGUCACAUAUUUAGG-5′ (SEQ ID NO: 4572) LDHA-1676 Target:5′-ACATCCTGGGATCCAGTGTATAAATCC-3′ (SEQ ID NO: 6586)5′-UCCUGGGAUCCAGUGUAUAAAUCca-3′ (SEQ ID NO: 2559)3′-GUAGGACCCUAGGUCACAUAUUUAGGU-5′ (SEQ ID NO: 4573) LDHA-1677 Target:5′-CATCCTGGGATCCAGTGTATAAATCCA-3′ (SEQ ID NO: 6587)5′-CCUGGGAUCCAGUGUAUAAAUCCaa-3′ (SEQ ID NO: 2560)3′-UAGGACCCUAGGUCACAUAUUUAGGUU-5′ (SEQ ID NO: 4574) LDHA-1678 Target:5′-ATCCTGGGATCCAGTGTATAAATCCAA-3′ (SEQ ID NO: 6588)5′-CUGGGAUCCAGUGUAUAAAUCCAat-3′ (SEQ ID NO: 2561)3′-AGGACCCUAGGUCACAUAUUUAGGUUA-5′ (SEQ ID NO: 4575) LDHA-1679 Target:5′-TCCTGGGATCCAGTGTATAAATCCAAT-3′ (SEQ ID NO: 6589)5′-UGGGAUCCAGUGUAUAAAUCCAAta-3′ (SEQ ID NO: 2562)3′-GGACCCUAGGUCACAUAUUUAGGUUAU-5′ (SEQ ID NO: 4576) LDHA-1680 Target:5′-CCTGGGATCCAGTGTATAAATCCAATA-3′ (SEQ ID NO: 6590)5′-GGGAUCCAGUGUAUAAAUCCAAUat-3′ (SEQ ID NO: 2563)3′-GACCCUAGGUCACAUAUUUAGGUUAUA-5′ (SEQ ID NO: 4577) LDHA-1681 Target:5′-CTGGGATCCAGTGTATAAATCCAATAT-3′ (SEQ ID NO: 6591)5′-GGAUCCAGUGUAUAAAUCCAAUAtc-3′ (SEQ ID NO: 2564)3′-ACCCUAGGUCACAUAUUUAGGUUAUAG-5′ (SEQ ID NO: 4578) LDHA-1682 Target:5′-TGGGATCCAGTGTATAAATCCAATATC-3′ (SEQ ID NO: 6592)5′-GAUCCAGUGUAUAAAUCCAAUAUca-3′ (SEQ ID NO: 2565)3′-CCCUAGGUCACAUAUUUAGGUUAUAGU-5′ (SEQ ID NO: 4579) LDHA-1683 Target:5′-GGGATCCAGTGTATAAATCCAATATCA-3′ (SEQ ID NO: 6593)5′-UCCAGUGUAUAAAUCCAAUAUCAtg-3′ (SEQ ID NO: 2566)3′-CUAGGUCACAUAUUUAGGUUAUAGUAC-5′ (SEQ ID NO: 4580) LDHA-1685 Target:5′-GATCCAGTGTATAAATCCAATATCATG-3′ (SEQ ID NO: 6594)5′-CCAGUGUAUAAAUCCAAUAUCAUgt-3′ (SEQ ID NO: 2567)3′-UAGGUCACAUAUUUAGGUUAUAGUACA-5′ (SEQ ID NO: 4581) LDHA-1686 Target:5′-ATCCAGTGTATAAATCCAATATCATGT-3′ (SEQ ID NO: 6595)5′-CAGUGUAUAAAUCCAAUAUCAUGtc-3′ (SEQ ID NO: 2568)3′-AGGUCACAUAUUUAGGUUAUAGUACAG-5′ (SEQ ID NO: 4582) LDHA-1687 Target:5′-TCCAGTGTATAAATCCAATATCATGTC-3′ (SEQ ID NO: 6596)5′-GUGUAUAAAUCCAAUAUCAUGUCtt-3′ (SEQ ID NO: 2569)3′-GUCACAUAUUUAGGUUAUAGUACAGAA-5′ (SEQ ID NO: 4583) LDHA-1689 Target:5′-CAGTGTATAAATCCAATATCATGTCTT-3′ (SEQ ID NO: 6597)5′-UGUAUAAAUCCAAUAUCAUGUCUtg-3′ (SEQ ID NO: 2570)3′-UCACAUAUUUAGGUUAUAGUACAGAAC-5′ (SEQ ID NO: 4584) LDHA-1690 Target:5′-AGTGTATAAATCCAATATCATGTCTTG-3′ (SEQ ID NO: 6598)5′-GUAUAAAUCCAAUAUCAUGUCUUgt-3′ (SEQ ID NO: 2571)3′-CACAUAUUUAGGUUAUAGUACAGAACA-5′ (SEQ ID NO: 4585) LDHA-1691 Target:5′-GTGTATAAATCCAATATCATGTCTTGT-3′ (SEQ ID NO: 6599)5′-UAUAAAUCCAAUAUCAUGUCUUGtg-3′ (SEQ ID NO: 2572)3′-ACAUAUUUAGGUUAUAGUACAGAACAC-5′ (SEQ ID NO: 4586) LDHA-1692 Target:5′-TGTATAAATCCAATATCATGTCTTGTG-3′ (SEQ ID NO: 6600)5′-AUAAAUCCAAUAUCAUGUCUUGUgc-3′ (SEQ ID NO: 2573)3′-CAUAUUUAGGUUAUAGUACAGAACACG-5′ (SEQ ID NO: 4587) LDHA-1693 Target:5′-GTATAAATCCAATATCATGTCTTGTGC-3′ (SEQ ID NO: 6601)5′-UAAAUCCAAUAUCAUGUCUUGUGca-3′ (SEQ ID NO: 2574)3′-AUAUUUAGGUUAUAGUACAGAACACGU-5′ (SEQ ID NO: 4588) LDHA-1694 Target:5′-TATAAATCCAATATCATGTCTTGTGCA-3′ (SEQ ID NO: 6602)5′-AAAUCCAAUAUCAUGUCUUGUGCat-3′ (SEQ ID NO: 2575)3′-UAUUUAGGUUAUAGUACAGAACACGUA-5′ (SEQ ID NO: 4589) LDHA-1695 Target:5′-ATAAATCCAATATCATGTCTTGTGCAT-3′ (SEQ ID NO: 6603)5′-AAUCCAAUAUCAUGUCUUGUGCAta-3′ (SEQ ID NO: 2576)3′-AUUUAGGUUAUAGUACAGAACACGUAU-5′ (SEQ ID NO: 4590) LDHA-1696 Target:5′-TAAATCCAATATCATGTCTTGTGCATA-3′ (SEQ ID NO: 6604)5′-AUCCAAUAUCAUGUCUUGUGCAUaa-3′ (SEQ ID NO: 2577)3′-UUUAGGUUAUAGUACAGAACACGUAUU-5′ (SEQ ID NO: 4591) LDHA-1697 Target:5′-AAATCCAATATCATGTCTTGTGCATAA-3′ (SEQ ID NO: 6605)5′-UCCAAUAUCAUGUCUUGUGCAUAat-3′ (SEQ ID NO: 2578)3′-UUAGGUUAUAGUACAGAACACGUAUUA-5′ (SEQ ID NO: 4592) LDHA-1698 Target:5′-AATCCAATATCATGTCTTGTGCATAAT-3′ (SEQ ID NO: 6606)5′-CCAAUAUCAUGUCUUGUGCAUAAtt-3′ (SEQ ID NO: 2579)3′-UAGGUUAUAGUACAGAACACGUAUUAA-5′ (SEQ ID NO: 4593) LDHA-1699 Target:5′-ATCCAATATCATGTCTTGTGCATAATT-3′ (SEQ ID NO: 6607)5′-CAAUAUCAUGUCUUGUGCAUAAUtc-3′ (SEQ ID NO: 2580)3′-AGGUUAUAGUACAGAACACGUAUUAAG-5′ (SEQ ID NO: 4594) LDHA-1700 Target:5′-TCCAATATCATGTCTTGTGCATAATTC-3′ (SEQ ID NO: 6608)5′-AAUAUCAUGUCUUGUGCAUAAUUct-3′ (SEQ ID NO: 2581)3′-GGUUAUAGUACAGAACACGUAUUAAGA-5′ (SEQ ID NO: 4595) LDHA-1701 Target:5′-CCAATATCATGTCTTGTGCATAATTCT-3′ (SEQ ID NO: 6609)5′-AUAUCAUGUCUUGUGCAUAAUUCtt-3′ (SEQ ID NO: 2582)3′-GUUAUAGUACAGAACACGUAUUAAGAA-5′ (SEQ ID NO: 4596) LDHA-1702 Target:5′-CAATATCATGTCTTGTGCATAATTCTT-3′ (SEQ ID NO: 6610)5′-UAUCAUGUCUUGUGCAUAAUUCUtc-3′ (SEQ ID NO: 2583)3′-UUAUAGUACAGAACACGUAUUAAGAAG-5′ (SEQ ID NO: 4597) LDHA-1703 Target:5′-AATATCATGTCTTGTGCATAATTCTTC-3′ (SEQ ID NO: 6611)5′-AUCAUGUCUUGUGCAUAAUUCUUcc-3′ (SEQ ID NO: 2584)3′-UAUAGUACAGAACACGUAUUAAGAAGG-5′ (SEQ ID NO: 4598) LDHA-1704 Target:5′-ATATCATGTCTTGTGCATAATTCTTCC-3′ (SEQ ID NO: 6612)5′-UCAUGUCUUGUGCAUAAUUCUUCca-3′ (SEQ ID NO: 2585)3′-AUAGUACAGAACACGUAUUAAGAAGGU-5′ (SEQ ID NO: 4599) LDHA-1705 Target:5′-TATCATGTCTTGTGCATAATTCTTCCA-3′ (SEQ ID NO: 6613)5′-CAUGUCUUGUGCAUAAUUCUUCCaa-3′ (SEQ ID NO: 2586)3′-UAGUACAGAACACGUAUUAAGAAGGUU-5′ (SEQ ID NO: 4600) LDHA-1706 Target:5′-ATCATGTCTTGTGCATAATTCTTCCAA-3′ (SEQ ID NO: 6614)5′-AUGUCUUGUGCAUAAUUCUUCCAaa-3′ (SEQ ID NO: 2587)3′-AGUACAGAACACGUAUUAAGAAGGUUU-5′ (SEQ ID NO: 4601) LDHA-1707 Target:5′-TCATGTCTTGTGCATAATTCTTCCAAA-3′ (SEQ ID NO: 6615)5′-UGUCUUGUGCAUAAUUCUUCCAAag-3′ (SEQ ID NO: 2588)3′-GUACAGAACACGUAUUAAGAAGGUUUC-5′ (SEQ ID NO: 4602) LDHA-1708 Target:5′-CATGTCTTGTGCATAATTCTTCCAAAG-3′ (SEQ ID NO: 6616)5′-GUCUUGUGCAUAAUUCUUCCAAAgg-3′ (SEQ ID NO: 2589)3′-UACAGAACACGUAUUAAGAAGGUUUCC-5′ (SEQ ID NO: 4603) LDHA-1709 Target:5′-ATGTCTTGTGCATAATTCTTCCAAAGG-3′ (SEQ ID NO: 6617)5′-UCUUGUGCAUAAUUCUUCCAAAGga-3′ (SEQ ID NO: 2590)3′-ACAGAACACGUAUUAAGAAGGUUUCCU-5′ (SEQ ID NO: 4604) LDHA-1710 Target:5′-TGTCTTGTGCATAATTCTTCCAAAGGA-3′ (SEQ ID NO: 6618)5′-CUUGUGCAUAAUUCUUCCAAAGGat-3′ (SEQ ID NO: 2591)3′-CAGAACACGUAUUAAGAAGGUUUCCUA-5′ (SEQ ID NO: 4605) LDHA-1711 Target:5′-GTCTTGTGCATAATTCTTCCAAAGGAT-3′ (SEQ ID NO: 6619)5′-UUGUGCAUAAUUCUUCCAAAGGAtc-3′ (SEQ ID NO: 2592)3′-AGAACACGUAUUAAGAAGGUUUCCUAG-5′ (SEQ ID NO: 4606) LDHA-1712 Target:5′-TCTTGTGCATAATTCTTCCAAAGGATC-3′ (SEQ ID NO: 6620)5′-UGUGCAUAAUUCUUCCAAAGGAUct-3′ (SEQ ID NO: 2593)3′-GAACACGUAUUAAGAAGGUUUCCUAGA-5′ (SEQ ID NO: 4607) LDHA-1713 Target:5′-CTTGTGCATAATTCTTCCAAAGGATCT-3′ (SEQ ID NO: 6621)5′-GUGCAUAAUUCUUCCAAAGGAUCtt-3′ (SEQ ID NO: 2594)3′-AACACGUAUUAAGAAGGUUUCCUAGAA-5′ (SEQ ID NO: 4608) LDHA-1714 Target:5′-TTGTGCATAATTCTTCCAAAGGATCTT-3′ (SEQ ID NO: 6622)5′-UGCAUAAUUCUUCCAAAGGAUCUta-3′ (SEQ ID NO: 2595)3′-ACACGUAUUAAGAAGGUUUCCUAGAAU-5′ (SEQ ID NO: 4609) LDHA-1715 Target:5′-TGTGCATAATTCTTCCAAAGGATCTTA-3′ (SEQ ID NO: 6623)5′-GCAUAAUUCUUCCAAAGGAUCUUat-3′ (SEQ ID NO: 2596)3′-CACGUAUUAAGAAGGUUUCCUAGAAUA-5′ (SEQ ID NO: 4610) LDHA-1716 Target:5′-GTGCATAATTCTTCCAAAGGATCTTAT-3′ (SEQ ID NO: 6624)5′-CAUAAUUCUUCCAAAGGAUCUUAtt-3′ (SEQ ID NO: 2597)3′-ACGUAUUAAGAAGGUUUCCUAGAAUAA-5′ (SEQ ID NO: 4611) LDHA-1717 Target:5′-TGCATAATTCTTCCAAAGGATCTTATT-3′ (SEQ ID NO: 6625)5′-AUAAUUCUUCCAAAGGAUCUUAUtt-3′ (SEQ ID NO: 2598)3′-CGUAUUAAGAAGGUUUCCUAGAAUAAA-5′ (SEQ ID NO: 4612) LDHA-1718 Target:5′-GCATAATTCTTCCAAAGGATCTTATTT-3′ (SEQ ID NO: 6626)5′-UAAUUCUUCCAAAGGAUCUUAUUtt-3′ (SEQ ID NO: 2599)3′-GUAUUAAGAAGGUUUCCUAGAAUAAAA-5′ (SEQ ID NO: 4613) LDHA-1719 Target:5′-CATAATTCTTCCAAAGGATCTTATTTT-3′ (SEQ ID NO: 6627)5′-AAUUCUUCCAAAGGAUCUUAUUUtg-3′ (SEQ ID NO: 2600)3′-UAUUAAGAAGGUUUCCUAGAAUAAAAC-5′ (SEQ ID NO: 4614) LDHA-1720 Target:5′-ATAATTCTTCCAAAGGATCTTATTTTG-3′ (SEQ ID NO: 6628)5′-AUUCUUCCAAAGGAUCUUAUUUUgt-3′ (SEQ ID NO: 2601)3′-AUUAAGAAGGUUUCCUAGAAUAAAACA-5′ (SEQ ID NO: 4615) LDHA-1721 Target:5′-TAATTCTTCCAAAGGATCTTATTTTGT-3′ (SEQ ID NO: 6629)5′-UUCUUCCAAAGGAUCUUAUUUUGtg-3′ (SEQ ID NO: 2602)3′-UUAAGAAGGUUUCCUAGAAUAAAACAC-5′ (SEQ ID NO: 4616) LDHA-1722 Target:5′-AATTCTTCCAAAGGATCTTATTTTGTG-3′ (SEQ ID NO: 6630)5′-UCUUCCAAAGGAUCUUAUUUUGUga-3′ (SEQ ID NO: 2603)3′-UAAGAAGGUUUCCUAGAAUAAAACACU-5′ (SEQ ID NO: 4617) LDHA-1723 Target:5′-ATTCTTCCAAAGGATCTTATTTTGTGA-3′ (SEQ ID NO: 6631)5′-CUUCCAAAGGAUCUUAUUUUGUGaa-3′ (SEQ ID NO: 2604)3′-AAGAAGGUUUCCUAGAAUAAAACACUU-5′ (SEQ ID NO: 4618) LDHA-1724 Target:5′-TTCTTCCAAAGGATCTTATTTTGTGAA-3′ (SEQ ID NO: 6632)5′-UUCCAAAGGAUCUUAUUUUGUGAac-3′ (SEQ ID NO: 2605)3′-AGAAGGUUUCCUAGAAUAAAACACUUG-5′ (SEQ ID NO: 4619) LDHA-1725 Target:5′-TCTTCCAAAGGATCTTATTTTGTGAAC-3′ (SEQ ID NO: 6633)5′-UCCAAAGGAUCUUAUUUUGUGAAct-3′ (SEQ ID NO: 2606)3′-GAAGGUUUCCUAGAAUAAAACACUUGA-5′ (SEQ ID NO: 4620) LDHA-1726 Target:5′-CTTCCAAAGGATCTTATTTTGTGAACT-3′ (SEQ ID NO: 6634)5′-CCAAAGGAUCUUAUUUUGUGAACta-3′ (SEQ ID NO: 2607)3′-AAGGUUUCCUAGAAUAAAACACUUGAU-5′ (SEQ ID NO: 4621) LDHA-1727 Target:5′-TTCCAAAGGATCTTATTTTGTGAACTA-3′ (SEQ ID NO: 6635)5′-CAAAGGAUCUUAUUUUGUGAACUat-3′ (SEQ ID NO: 2608)3′-AGGUUUCCUAGAAUAAAACACUUGAUA-5′ (SEQ ID NO: 4622) LDHA-1728 Target:5′-TCCAAAGGATCTTATTTTGTGAACTAT-3′ (SEQ ID NO: 6636)5′-AAAGGAUCUUAUUUUGUGAACUAta-3′ (SEQ ID NO: 2609)3′-GGUUUCCUAGAAUAAAACACUUGAUAU-5′ (SEQ ID NO: 4623) LDHA-1729 Target:5′-CCAAAGGATCTTATTTTGTGAACTATA-3′ (SEQ ID NO: 6637)5′-AAGGAUCUUAUUUUGUGAACUAUat-3′ (SEQ ID NO: 2610)3′-GUUUCCUAGAAUAAAACACUUGAUAUA-5′ (SEQ ID NO: 4624) LDHA-1730 Target:5′-CAAAGGATCTTATTTTGTGAACTATAT-3′ (SEQ ID NO: 6638)5′-AGGAUCUUAUUUUGUGAACUAUAtc-3′ (SEQ ID NO: 2611)3′-UUUCCUAGAAUAAAACACUUGAUAUAG-5′ (SEQ ID NO: 4625) LDHA-1731 Target:5′-AAAGGATCTTATTTTGTGAACTATATC-3′ (SEQ ID NO: 6639)5′-GGAUCUUAUUUUGUGAACUAUAUca-3′ (SEQ ID NO: 2612)3′-UUCCUAGAAUAAAACACUUGAUAUAGU-5′ (SEQ ID NO: 4626) LDHA-1732 Target:5′-AAGGATCTTATTTTGTGAACTATATCA-3′ (SEQ ID NO: 6640)5′-GAUCUUAUUUUGUGAACUAUAUCag-3′ (SEQ ID NO: 2613)3′-UCCUAGAAUAAAACACUUGAUAUAGUC-5′ (SEQ ID NO: 4627) LDHA-1733 Target:5′-AGGATCTTATTTTGTGAACTATATCAG-3′ (SEQ ID NO: 6641)5′-AUCUUAUUUUGUGAACUAUAUCAgt-3′ (SEQ ID NO: 2614)3′-CCUAGAAUAAAACACUUGAUAUAGUCA-5′ (SEQ ID NO: 4628) LDHA-1734 Target:5′-GGATCTTATTTTGTGAACTATATCAGT-3′ (SEQ ID NO: 6642)5′-UCUUAUUUUGUGAACUAUAUCAGta-3′ (SEQ ID NO: 2615)3′-CUAGAAUAAAACACUUGAUAUAGUCAU-5′ (SEQ ID NO: 4629) LDHA-1735 Target:5′-GATCTTATTTTGTGAACTATATCAGTA-3′ (SEQ ID NO: 6643)5′-UUAUUUUGUGAACUAUAUCAGUAgt-3′ (SEQ ID NO: 2616)3′-AGAAUAAAACACUUGAUAUAGUCAUCA-5′ (SEQ ID NO: 4630) LDHA-1737 Target:5′-TCTTATTTTGTGAACTATATCAGTAGT-3′ (SEQ ID NO: 6644)5′-UAUUUUGUGAACUAUAUCAGUAGtg-3′ (SEQ ID NO: 2617)3′-GAAUAAAACACUUGAUAUAGUCAUCAC-5′ (SEQ ID NO: 4631) LDHA-1738 Target:5′-CTTATTTTGTGAACTATATCAGTAGTG-3′ (SEQ ID NO: 6645)5′-AUUUUGUGAACUAUAUCAGUAGUgt-3′ (SEQ ID NO: 2618)3′-AAUAAAACACUUGAUAUAGUCAUCACA-5′ (SEQ ID NO: 4632) LDHA-1739 Target:5′-TTATTTTGTGAACTATATCAGTAGTGT-3′ (SEQ ID NO: 6646)5′-UUUUGUGAACUAUAUCAGUAGUGta-3′ (SEQ ID NO: 2619)3′-AUAAAACACUUGAUAUAGUCAUCACAU-5′ (SEQ ID NO: 4633) LDHA-1740 Target:5′-TATTTTGTGAACTATATCAGTAGTGTA-3′ (SEQ ID NO: 6647)5′-UUUGUGAACUAUAUCAGUAGUGUac-3′ (SEQ ID NO: 2620)3′-UAAAACACUUGAUAUAGUCAUCACAUG-5′ (SEQ ID NO: 4634) LDHA-1741 Target:5′-ATTTTGTGAACTATATCAGTAGTGTAC-3′ (SEQ ID NO: 6648)5′-UUGUGAACUAUAUCAGUAGUGUAca-3′ (SEQ ID NO: 2621)3′-AAAACACUUGAUAUAGUCAUCACAUGU-5′ (SEQ ID NO: 4635) LDHA-1742 Target:5′-TTTTGTGAACTATATCAGTAGTGTACA-3′ (SEQ ID NO: 6649)5′-UGUGAACUAUAUCAGUAGUGUACat-3′ (SEQ ID NO: 2622)3′-AAACACUUGAUAUAGUCAUCACAUGUA-5′ (SEQ ID NO: 4636) LDHA-1743 Target:5′-TTTGTGAACTATATCAGTAGTGTACAT-3′ (SEQ ID NO: 6650)5′-GUGAACUAUAUCAGUAGUGUACAtt-3′ (SEQ ID NO: 2623)3′-AACACUUGAUAUAGUCAUCACAUGUAA-5′ (SEQ ID NO: 4637) LDHA-1744 Target:5′-TTGTGAACTATATCAGTAGTGTACATT-3′ (SEQ ID NO: 6651)5′-UGAACUAUAUCAGUAGUGUACAUta-3′ (SEQ ID NO: 2624)3′-ACACUUGAUAUAGUCAUCACAUGUAAU-5′ (SEQ ID NO: 4638) LDHA-1745 Target:5′-TGTGAACTATATCAGTAGTGTACATTA-3′ (SEQ ID NO: 6652)5′-GAACUAUAUCAGUAGUGUACAUUac-3′ (SEQ ID NO: 2625)3′-CACUUGAUAUAGUCAUCACAUGUAAUG-5′ (SEQ ID NO: 4639) LDHA-1746 Target:5′-GTGAACTATATCAGTAGTGTACATTAC-3′ (SEQ ID NO: 6653)5′-AACUAUAUCAGUAGUGUACAUUAcc-3′ (SEQ ID NO: 2626)3′-ACUUGAUAUAGUCAUCACAUGUAAUGG-5′ (SEQ ID NO: 4640) LDHA-1747 Target:5′-TGAACTATATCAGTAGTGTACATTACC-3′ (SEQ ID NO: 6654)5′-ACUAUAUCAGUAGUGUACAUUACca-3′ (SEQ ID NO: 2627)3′-CUUGAUAUAGUCAUCACAUGUAAUGGU-5′ (SEQ ID NO: 4641) LDHA-1748 Target:5′-GAACTATATCAGTAGTGTACATTACCA-3′ (SEQ ID NO: 6655)5′-CUAUAUCAGUAGUGUACAUUACCat-3′ (SEQ ID NO: 2628)3′-UUGAUAUAGUCAUCACAUGUAAUGGUA-5′ (SEQ ID NO: 4642) LDHA-1749 Target:5′-AACTATATCAGTAGTGTACATTACCAT-3′ (SEQ ID NO: 6656)5′-AUAUCAGUAGUGUACAUUACCAUat-3′ (SEQ ID NO: 2629)3′-GAUAUAGUCAUCACAUGUAAUGGUAUA-5′ (SEQ ID NO: 4643) LDHA-1751 Target:5′-CTATATCAGTAGTGTACATTACCATAT-3′ (SEQ ID NO: 6657)5′-UAUCAGUAGUGUACAUUACCAUAta-3′ (SEQ ID NO: 2630)3′-AUAUAGUCAUCACAUGUAAUGGUAUAU-5′ (SEQ ID NO: 4644) LDHA-1752 Target:5′-TATATCAGTAGTGTACATTACCATATA-3′ (SEQ ID NO: 6658)5′-CAGUAGUGUACAUUACCAUAUAAtg-3′ (SEQ ID NO: 2631)3′-UAGUCAUCACAUGUAAUGGUAUAUUAC-5′ (SEQ ID NO: 4645) LDHA-1755 Target:5′-ATCAGTAGTGTACATTACCATATAATG-3′ (SEQ ID NO: 6659)5′-AGUAGUGUACAUUACCAUAUAAUgt-3′ (SEQ ID NO: 2632)3′-AGUCAUCACAUGUAAUGGUAUAUUACA-5′ (SEQ ID NO: 4646) LDHA-1756 Target:5′-TCAGTAGTGTACATTACCATATAATGT-3′ (SEQ ID NO: 6660)5′-GUAGUGUACAUUACCAUAUAAUGta-3′ (SEQ ID NO: 2633)3′-GUCAUCACAUGUAAUGGUAUAUUACAU-5′ (SEQ ID NO: 4647) LDHA-1757 Target:5′-CAGTAGTGTACATTACCATATAATGTA-3′ (SEQ ID NO: 6661)5′-UAGUGUACAUUACCAUAUAAUGUaa-3′ (SEQ ID NO: 2634)3′-UCAUCACAUGUAAUGGUAUAUUACAUU-5′ (SEQ ID NO: 4648) LDHA-1758 Target:5′-AGTAGTGTACATTACCATATAATGTAA-3′ (SEQ ID NO: 6662)5′-AGUGUACAUUACCAUAUAAUGUAaa-3′ (SEQ ID NO: 2635)3′-CAUCACAUGUAAUGGUAUAUUACAUUU-5′ (SEQ ID NO: 4649) LDHA-1759 Target:5′-GTAGTGTACATTACCATATAATGTAAA-3′ (SEQ ID NO: 6663)5′-GUGUACAUUACCAUAUAAUGUAAaa-3′ (SEQ ID NO: 2636)3′-AUCACAUGUAAUGGUAUAUUACAUUUU-5′ (SEQ ID NO: 4650) LDHA-1760 Target:5′-TAGTGTACATTACCATATAATGTAAAA-3′ (SEQ ID NO: 6664)5′-UGUACAUUACCAUAUAAUGUAAAaa-3′ (SEQ ID NO: 2637)3′-UCACAUGUAAUGGUAUAUUACAUUUUU-5′ (SEQ ID NO: 4651) LDHA-1761 Target:5′-AGTGTACATTACCATATAATGTAAAAA-3′ (SEQ ID NO: 6665)5′-GUACAUUACCAUAUAAUGUAAAAag-3′ (SEQ ID NO: 2638)3′-CACAUGUAAUGGUAUAUUACAUUUUUC-5′ (SEQ ID NO: 4652) LDHA-1762 Target:5′-GTGTACATTACCATATAATGTAAAAAG-3′ (SEQ ID NO: 6666)5′-UACAUUACCAUAUAAUGUAAAAAga-3′ (SEQ ID NO: 2639)3′-ACAUGUAAUGGUAUAUUACAUUUUUCU-5′ (SEQ ID NO: 4653) LDHA-1763 Target:5′-TGTACATTACCATATAATGTAAAAAGA-3′ (SEQ ID NO: 6667)5′-ACAUUACCAUAUAAUGUAAAAAGat-3′ (SEQ ID NO: 2640)3′-CAUGUAAUGGUAUAUUACAUUUUUCUA-5′ (SEQ ID NO: 4654) LDHA-1764 Target:5′-GTACATTACCATATAATGTAAAAAGAT-3′ (SEQ ID NO: 6668)5′-CAUUACCAUAUAAUGUAAAAAGAtc-3′ (SEQ ID NO: 2641)3′-AUGUAAUGGUAUAUUACAUUUUUCUAG-5′ (SEQ ID NO: 4655) LDHA-1765 Target:5′-TACATTACCATATAATGTAAAAAGATC-3′ (SEQ ID NO: 6669)5′-AUUACCAUAUAAUGUAAAAAGAUct-3′ (SEQ ID NO: 2642)3′-UGUAAUGGUAUAUUACAUUUUUCUAGA-5′ (SEQ ID NO: 4656) LDHA-1766 Target:5′-ACATTACCATATAATGTAAAAAGATCT-3′ (SEQ ID NO: 6670)5′-UUACCAUAUAAUGUAAAAAGAUCta-3′ (SEQ ID NO: 2643)3′-GUAAUGGUAUAUUACAUUUUUCUAGAU-5′ (SEQ ID NO: 4657) LDHA-1767 Target:5′-CATTACCATATAATGTAAAAAGATCTA-3′ (SEQ ID NO: 6671)5′-UACCAUAUAAUGUAAAAAGAUCUac-3′ (SEQ ID NO: 2644)3′-UAAUGGUAUAUUACAUUUUUCUAGAUG-5′ (SEQ ID NO: 4658) LDHA-1768 Target:5′-ATTACCATATAATGTAAAAAGATCTAC-3′ (SEQ ID NO: 6672)5′-ACCAUAUAAUGUAAAAAGAUCUAca-3′ (SEQ ID NO: 2645)3′-AAUGGUAUAUUACAUUUUUCUAGAUGU-5′ (SEQ ID NO: 4659) LDHA-1769 Target:5′-TTACCATATAATGTAAAAAGATCTACA-3′ (SEQ ID NO: 6673)5′-CCAUAUAAUGUAAAAAGAUCUACat-3′ (SEQ ID NO: 2646)3′-AUGGUAUAUUACAUUUUUCUAGAUGUA-5′ (SEQ ID NO: 4660) LDHA-1770 Target:5′-TACCATATAATGTAAAAAGATCTACAT-3′ (SEQ ID NO: 6674)5′-CAUAUAAUGUAAAAAGAUCUACAta-3′ (SEQ ID NO: 2647)3′-UGGUAUAUUACAUUUUUCUAGAUGUAU-5′ (SEQ ID NO: 4661) LDHA-1771 Target:5′-ACCATATAATGTAAAAAGATCTACATA-3′ (SEQ ID NO: 6675)5′-AUAUAAUGUAAAAAGAUCUACAUac-3′ (SEQ ID NO: 2648)3′-GGUAUAUUACAUUUUUCUAGAUGUAUG-5′ (SEQ ID NO: 4662) LDHA-1772 Target:5′-CCATATAATGTAAAAAGATCTACATAC-3′ (SEQ ID NO: 6676)5′-UAUAAUGUAAAAAGAUCUACAUAca-3′ (SEQ ID NO: 2649)3′-GUAUAUUACAUUUUUCUAGAUGUAUGU-5′ (SEQ ID NO: 4663) LDHA-1773 Target:5′-CATATAATGTAAAAAGATCTACATACA-3′ (SEQ ID NO: 6677)5′-AUAAUGUAAAAAGAUCUACAUACaa-3′ (SEQ ID NO: 2650)3′-UAUAUUACAUUUUUCUAGAUGUAUGUU-5′ (SEQ ID NO: 4664) LDHA-1774 Target:5′-ATATAATGTAAAAAGATCTACATACAA-3′ (SEQ ID NO: 6678)5′-UAAUGUAAAAAGAUCUACAUACAaa-3′ (SEQ ID NO: 2651)3′-AUAUUACAUUUUUCUAGAUGUAUGUUU-5′ (SEQ ID NO: 4665) LDHA-1775 Target:5′-TATAATGTAAAAAGATCTACATACAAA-3′ (SEQ ID NO: 6679)5′-AAUGUAAAAAGAUCUACAUACAAac-3′ (SEQ ID NO: 2652)3′-UAUUACAUUUUUCUAGAUGUAUGUUUG-5′ (SEQ ID NO: 4666) LDHA-1776 Target:5′-ATAATGTAAAAAGATCTACATACAAAC-3′ (SEQ ID NO: 6680)5′-AUGUAAAAAGAUCUACAUACAAAca-3′ (SEQ ID NO: 2653)3′-AUUACAUUUUUCUAGAUGUAUGUUUGU-5′ (SEQ ID NO: 4667) LDHA-1777 Target:5′-TAATGTAAAAAGATCTACATACAAACA-3′ (SEQ ID NO: 6681)5′-UGUAAAAAGAUCUACAUACAAACaa-3′ (SEQ ID NO: 2654)3′-UUACAUUUUUCUAGAUGUAUGUUUGUU-5′ (SEQ ID NO: 4668) LDHA-1778 Target:5′-AATGTAAAAAGATCTACATACAAACAA-3′ (SEQ ID NO: 6682)5′-GUAAAAAGAUCUACAUACAAACAat-3′ (SEQ ID NO: 2655)3′-UACAUUUUUCUAGAUGUAUGUUUGUUA-5′ (SEQ ID NO: 4669) LDHA-1779 Target:5′-ATGTAAAAAGATCTACATACAAACAAT-3′ (SEQ ID NO: 6683)5′-UAAAAAGAUCUACAUACAAACAAtg-3′ (SEQ ID NO: 2656)3′-ACAUUUUUCUAGAUGUAUGUUUGUUAC-5′ (SEQ ID NO: 4670) LDHA-1780 Target:5′-TGTAAAAAGATCTACATACAAACAATG-3′ (SEQ ID NO: 6684)5′-AAAAAGAUCUACAUACAAACAAUgc-3′ (SEQ ID NO: 2657)3′-CAUUUUUCUAGAUGUAUGUUUGUUACG-5′ (SEQ ID NO: 4671) LDHA-1781 Target:5′-GTAAAAAGATCTACATACAAACAATGC-3′ (SEQ ID NO: 6685)5′-AAAAGAUCUACAUACAAACAAUGca-3′ (SEQ ID NO: 2658)3′-AUUUUUCUAGAUGUAUGUUUGUUACGU-5′ (SEQ ID NO: 4672) LDHA-1782 Target:5′-TAAAAAGATCTACATACAAACAATGCA-3′ (SEQ ID NO: 6686)5′-AAAGAUCUACAUACAAACAAUGCaa-3′ (SEQ ID NO: 2659)3′-UUUUUCUAGAUGUAUGUUUGUUACGUU-5′ (SEQ ID NO: 4673) LDHA-1783 Target:5′-AAAAAGATCTACATACAAACAATGCAA-3′ (SEQ ID NO: 6687)5′-AAGAUCUACAUACAAACAAUGCAac-3′ (SEQ ID NO: 2660)3′-UUUUCUAGAUGUAUGUUUGUUACGUUG-5′ (SEQ ID NO: 4674) LDHA-1784 Target:5′-AAAAGATCTACATACAAACAATGCAAC-3′ (SEQ ID NO: 6688)5′-AGAUCUACAUACAAACAAUGCAAcc-3′ (SEQ ID NO: 2661)3′-UUUCUAGAUGUAUGUUUGUUACGUUGG-5′ (SEQ ID NO: 4675) LDHA-1785 Target:5′-AAAGATCTACATACAAACAATGCAACC-3′ (SEQ ID NO: 6689)5′-GAUCUACAUACAAACAAUGCAACca-3′ (SEQ ID NO: 2662)3′-UUCUAGAUGUAUGUUUGUUACGUUGGU-5′ (SEQ ID NO: 4676) LDHA-1786 Target:5′-AAGATCTACATACAAACAATGCAACCA-3′ (SEQ ID NO: 6690)5′-AUCUACAUACAAACAAUGCAACCaa-3′ (SEQ ID NO: 2663)3′-UCUAGAUGUAUGUUUGUUACGUUGGUU-5′ (SEQ ID NO: 4677) LDHA-1787 Target:5′-AGATCTACATACAAACAATGCAACCAA-3′ (SEQ ID NO: 6691)5′-UCUACAUACAAACAAUGCAACCAac-3′ (SEQ ID NO: 2664)3′-CUAGAUGUAUGUUUGUUACGUUGGUUG-5′ (SEQ ID NO: 4678) LDHA-1788 Target:5′-GATCTACATACAAACAATGCAACCAAC-3′ (SEQ ID NO: 6692)5′-CUACAUACAAACAAUGCAACCAAct-3′ (SEQ ID NO: 2665)3′-UAGAUGUAUGUUUGUUACGUUGGUUGA-5′ (SEQ ID NO: 4679) LDHA-1789 Target:5′-ATCTACATACAAACAATGCAACCAACT-3′ (SEQ ID NO: 6693)5′-UACAUACAAACAAUGCAACCAACta-3′ (SEQ ID NO: 2666)3′-AGAUGUAUGUUUGUUACGUUGGUUGAU-5′ (SEQ ID NO: 4680) LDHA-1790 Target:5′-TCTACATACAAACAATGCAACCAACTA-3′ (SEQ ID NO: 6694)5′-ACAUACAAACAAUGCAACCAACUat-3′ (SEQ ID NO: 2667)3′-GAUGUAUGUUUGUUACGUUGGUUGAUA-5′ (SEQ ID NO: 4681) LDHA-1791 Target:5′-CTACATACAAACAATGCAACCAACTAT-3′ (SEQ ID NO: 6695)5′-CAUACAAACAAUGCAACCAACUAtc-3′ (SEQ ID NO: 2668)3′-AUGUAUGUUUGUUACGUUGGUUGAUAG-5′ (SEQ ID NO: 4682) LDHA-1792 Target:5′-TACATACAAACAATGCAACCAACTATC-3′ (SEQ ID NO: 6696)5′-AUACAAACAAUGCAACCAACUAUcc-3′ (SEQ ID NO: 2669)3′-UGUAUGUUUGUUACGUUGGUUGAUAGG-5′ (SEQ ID NO: 4683) LDHA-1793 Target:5′-ACATACAAACAATGCAACCAACTATCC-3′ (SEQ ID NO: 6697)5′-UACAAACAAUGCAACCAACUAUCca-3′ (SEQ ID NO: 2670)3′-GUAUGUUUGUUACGUUGGUUGAUAGGU-5′ (SEQ ID NO: 4684) LDHA-1794 Target:5′-CATACAAACAATGCAACCAACTATCCA-3′ (SEQ ID NO: 6698)5′-ACAAACAAUGCAACCAACUAUCCaa-3′ (SEQ ID NO: 2671)3′-UAUGUUUGUUACGUUGGUUGAUAGGUU-5′ (SEQ ID NO: 4685) LDHA-1795 Target:5′-ATACAAACAATGCAACCAACTATCCAA-3′ (SEQ ID NO: 6699)5′-CAAACAAUGCAACCAACUAUCCAag-3′ (SEQ ID NO: 2672)3′-AUGUUUGUUACGUUGGUUGAUAGGUUC-5′ (SEQ ID NO: 4686) LDHA-1796 Target:5′-TACAAACAATGCAACCAACTATCCAAG-3′ (SEQ ID NO: 6700)5′-AAACAAUGCAACCAACUAUCCAAgt-3′ (SEQ ID NO: 2673)3′-UGUUUGUUACGUUGGUUGAUAGGUUCA-5′ (SEQ ID NO: 4687) LDHA-1797 Target:5′-ACAAACAATGCAACCAACTATCCAAGT-3′ (SEQ ID NO: 6701)5′-AACAAUGCAACCAACUAUCCAAGtg-3′ (SEQ ID NO: 2674)3′-GUUUGUUACGUUGGUUGAUAGGUUCAC-5′ (SEQ ID NO: 4688) LDHA-1798 Target:5′-CAAACAATGCAACCAACTATCCAAGTG-3′ (SEQ ID NO: 6702)5′-ACAAUGCAACCAACUAUCCAAGUgt-3′ (SEQ ID NO: 2675)3′-UUUGUUACGUUGGUUGAUAGGUUCACA-5′ (SEQ ID NO: 4689) LDHA-1799 Target:5′-AAACAATGCAACCAACTATCCAAGTGT-3′ (SEQ ID NO: 6703)5′-CAAUGCAACCAACUAUCCAAGUGtt-3′ (SEQ ID NO: 2676)3′-UUGUUACGUUGGUUGAUAGGUUCACAA-5′ (SEQ ID NO: 4690) LDHA-1800 Target:5′-AACAATGCAACCAACTATCCAAGTGTT-3′ (SEQ ID NO: 6704)5′-AAUGCAACCAACUAUCCAAGUGUta-3′ (SEQ ID NO: 2677)3′-UGUUACGUUGGUUGAUAGGUUCACAAU-5′ (SEQ ID NO: 4691) LDHA-1801 Target:5′-ACAATGCAACCAACTATCCAAGTGTTA-3′ (SEQ ID NO: 6705)5′-AUGCAACCAACUAUCCAAGUGUUat-3′ (SEQ ID NO: 2678)3′-GUUACGUUGGUUGAUAGGUUCACAAUA-5′ (SEQ ID NO: 4692) LDHA-1802 Target:5′-CAATGCAACCAACTATCCAAGTGTTAT-3′ (SEQ ID NO: 6706)5′-UGCAACCAACUAUCCAAGUGUUAta-3′ (SEQ ID NO: 2679)3′-UUACGUUGGUUGAUAGGUUCACAAUAU-5′ (SEQ ID NO: 4693) LDHA-1803 Target:5′-AATGCAACCAACTATCCAAGTGTTATA-3′ (SEQ ID NO: 6707)5′-GCAACCAACUAUCCAAGUGUUAUac-3′ (SEQ ID NO: 2680)3′-UACGUUGGUUGAUAGGUUCACAAUAUG-5′ (SEQ ID NO: 4694) LDHA-1804 Target:5′-ATGCAACCAACTATCCAAGTGTTATAC-3′ (SEQ ID NO: 6708)5′-CAACUAUCCAAGUGUUAUACCAAct-3′ (SEQ ID NO: 2681)3′-UGGUUGAUAGGUUCACAAUAUGGUUGA-5′ (SEQ ID NO: 4695) LDHA-1809 Target:5′-ACCAACTATCCAAGTGTTATACCAACT-3′ (SEQ ID NO: 6709)5′-AACUAUCCAAGUGUUAUACCAACta-3′ (SEQ ID NO: 2682)3′-GGUUGAUAGGUUCACAAUAUGGUUGAU-5′ (SEQ ID NO: 4696) LDHA-1810 Target:5′-CCAACTATCCAAGTGTTATACCAACTA-3′ (SEQ ID NO: 6710)5′-UAUCCAAGUGUUAUACCAACUAAaa-3′ (SEQ ID NO: 2683)3′-UGAUAGGUUCACAAUAUGGUUGAUUUU-5′ (SEQ ID NO: 4697) LDHA-1813 Target:5′-ACTATCCAAGTGTTATACCAACTAAAA-3′ (SEQ ID NO: 6711)5′-AUCCAAGUGUUAUACCAACUAAAac-3′ (SEQ ID NO: 2684)3′-GAUAGGUUCACAAUAUGGUUGAUUUUG-5′ (SEQ ID NO: 4698) LDHA-1814 Target:5′-CTATCCAAGTGTTATACCAACTAAAAC-3′ (SEQ ID NO: 6712)5′-CAAGUGUUAUACCAACUAAAACCcc-3′ (SEQ ID NO: 2685)3′-AGGUUCACAAUAUGGUUGAUUUUGGGG-5′ (SEQ ID NO: 4699) LDHA-1817 Target:5′-TCCAAGTGTTATACCAACTAAAACCCC-3′ (SEQ ID NO: 6713)5′-AAGUGUUAUACCAACUAAAACCCcc-3′ (SEQ ID NO: 2686)3′-GGUUCACAAUAUGGUUGAUUUUGGGGG-5′ (SEQ ID NO: 4700) LDHA-1818 Target:5′-CCAAGTGTTATACCAACTAAAACCCCC-3′ (SEQ ID NO: 6714)5′-AGUGUUAUACCAACUAAAACCCCca-3′ (SEQ ID NO: 2687)3′-GUUCACAAUAUGGUUGAUUUUGGGGGU-5′ (SEQ ID NO: 4701) LDHA-1819 Target:5′-CAAGTGTTATACCAACTAAAACCCCCA-3′ (SEQ ID NO: 6715)5′-GUGUUAUACCAACUAAAACCCCCaa-3′ (SEQ ID NO: 2688)3′-UUCACAAUAUGGUUGAUUUUGGGGGUU-5′ (SEQ ID NO: 4702) LDHA-1820 Target:5′-AAGTGTTATACCAACTAAAACCCCCAA-3′ (SEQ ID NO: 6716)5′-UGUUAUACCAACUAAAACCCCCAat-3′ (SEQ ID NO: 2689)3′-UCACAAUAUGGUUGAUUUUGGGGGUUA-5′ (SEQ ID NO: 4703) LDHA-1821 Target:5′-AGTGTTATACCAACTAAAACCCCCAAT-3′ (SEQ ID NO: 6717)5′-GUUAUACCAACUAAAACCCCCAAta-3′ (SEQ ID NO: 2690)3′-CACAAUAUGGUUGAUUUUGGGGGUUAU-5′ (SEQ ID NO: 4704) LDHA-1822 Target:5′-GTGTTATACCAACTAAAACCCCCAATA-3′ (SEQ ID NO: 6718)5′-UUAUACCAACUAAAACCCCCAAUaa-3′ (SEQ ID NO: 2691)3′-ACAAUAUGGUUGAUUUUGGGGGUUAUU-5′ (SEQ ID NO: 4705) LDHA-1823 Target:5′-TGTTATACCAACTAAAACCCCCAATAA-3′ (SEQ ID NO: 6719)5′-UAUACCAACUAAAACCCCCAAUAaa-3′ (SEQ ID NO: 2692)3′-CAAUAUGGUUGAUUUUGGGGGUUAUUU-5′ (SEQ ID NO: 4706) LDHA-1824 Target:5′-GTTATACCAACTAAAACCCCCAATAAA-3′ (SEQ ID NO: 6720)5′-AUACCAACUAAAACCCCCAAUAAac-3′ (SEQ ID NO: 2693)3′-AAUAUGGUUGAUUUUGGGGGUUAUUUG-5′ (SEQ ID NO: 4707) LDHA-1825 Target:5′-TTATACCAACTAAAACCCCCAATAAAC-3′ (SEQ ID NO: 6721)5′-UACCAACUAAAACCCCCAAUAAAcc-3′ (SEQ ID NO: 2694)3′-AUAUGGUUGAUUUUGGGGGUUAUUUGG-5′ (SEQ ID NO: 4708) LDHA-1826 Target:5′-TATACCAACTAAAACCCCCAATAAACC-3′ (SEQ ID NO: 6722)5′-ACCAACUAAAACCCCCAAUAAACct-3′ (SEQ ID NO: 2695)3′-UAUGGUUGAUUUUGGGGGUUAUUUGGA-5′ (SEQ ID NO: 4709) LDHA-1827 Target:5′-ATACCAACTAAAACCCCCAATAAACCT-3′ (SEQ ID NO: 6723)5′-CCAACUAAAACCCCCAAUAAACCtt-3′ (SEQ ID NO: 2696)3′-AUGGUUGAUUUUGGGGGUUAUUUGGAA-5′ (SEQ ID NO: 4710) LDHA-1828 Target:5′-TACCAACTAAAACCCCCAATAAACCTT-3′ (SEQ ID NO: 6724)5′-CAACUAAAACCCCCAAUAAACCUtg-3′ (SEQ ID NO: 2697)3′-UGGUUGAUUUUGGGGGUUAUUUGGAAC-5′ (SEQ ID NO: 4711) LDHA-1829 Target:5′-ACCAACTAAAACCCCCAATAAACCTTG-3′ (SEQ ID NO: 6725)5′-AACUAAAACCCCCAAUAAACCUUga-3′ (SEQ ID NO: 2698)3′-GGUUGAUUUUGGGGGUUAUUUGGAACU-5′ (SEQ ID NO: 4712) LDHA-1830 Target:5′-CCAACTAAAACCCCCAATAAACCTTGA-3′ (SEQ ID NO: 6726)5′-ACUAAAACCCCCAAUAAACCUUGaa-3′ (SEQ ID NO: 2699)3′-GUUGAUUUUGGGGGUUAUUUGGAACUU-5′ (SEQ ID NO: 4713) LDHA-1831 Target:5′-CAACTAAAACCCCCAATAAACCTTGAA-3′ (SEQ ID NO: 6727)5′-CUAAAACCCCCAAUAAACCUUGAac-3′ (SEQ ID NO: 2700)3′-UUGAUUUUGGGGGUUAUUUGGAACUUG-5′ (SEQ ID NO: 4714) LDHA-1832 Target:5′-AACTAAAACCCCCAATAAACCTTGAAC-3′ (SEQ ID NO: 6728)5′-UAAAACCCCCAAUAAACCUUGAAca-3′ (SEQ ID NO: 2701)3′-UGAUUUUGGGGGUUAUUUGGAACUUGU-5′ (SEQ ID NO: 4715) LDHA-1833 Target:5′-ACTAAAACCCCCAATAAACCTTGAACA-3′ (SEQ ID NO: 6729)5′-AAAACCCCCAAUAAACCUUGAACag-3′ (SEQ ID NO: 2702)3′-GAUUUUGGGGGUUAUUUGGAACUUGUC-5′ (SEQ ID NO: 4716) LDHA-1834 Target:5′-CTAAAACCCCCAATAAACCTTGAACAG-3′ (SEQ ID NO: 6730)5′-AAACCCCCAAUAAACCUUGAACAgt-3′ (SEQ ID NO: 2703)3′-AUUUUGGGGGUUAUUUGGAACUUGUCA-5′ (SEQ ID NO: 4717) LDHA-1835 Target:5′-TAAAACCCCCAATAAACCTTGAACAGT-3′ (SEQ ID NO: 6731)5′-AACCCCCAAUAAACCUUGAACAGtg-3′ (SEQ ID NO: 2704)3′-UUUUGGGGGUUAUUUGGAACUUGUCAC-5′ (SEQ ID NO: 4718) LDHA-1836 Target:5′-AAAACCCCCAATAAACCTTGAACAGTG-3′ (SEQ ID NO: 6732)5′-ACCCCCAAUAAACCUUGAACAGUga-3′ (SEQ ID NO: 2705)3′-UUUGGGGGUUAUUUGGAACUUGUCACU-5′ (SEQ ID NO: 4719) LDHA-1837 Target:5′-AAACCCCCAATAAACCTTGAACAGTGA-3′ (SEQ ID NO: 6733)5′-CCCCCAAUAAACCUUGAACAGUGac-3′ (SEQ ID NO: 2706)3′-UUGGGGGUUAUUUGGAACUUGUCACUG-5′ (SEQ ID NO: 4720) LDHA-1838 Target:5′-AACCCCCAATAAACCTTGAACAGTGAC-3′ (SEQ ID NO: 6734)5′-CCCCAAUAAACCUUGAACAGUGAct-3′ (SEQ ID NO: 2707)3′-UGGGGGUUAUUUGGAACUUGUCACUGA-5′ (SEQ ID NO: 4721) LDHA-1839 Target:5′-ACCCCCAATAAACCTTGAACAGTGACT-3′ (SEQ ID NO: 6735)5′-CCCAAUAAACCUUGAACAGUGACta-3′ (SEQ ID NO: 2708)3′-GGGGGUUAUUUGGAACUUGUCACUGAU-5′ (SEQ ID NO: 4722) LDHA-1840 Target:5′-CCCCCAATAAACCTTGAACAGTGACTA-3′ (SEQ ID NO: 6736)5′-CCAAUAAACCUUGAACAGUGACUac-3′ (SEQ ID NO: 2709)3′-GGGGUUAUUUGGAACUUGUCACUGAUG-5′ (SEQ ID NO: 4723) LDHA-1841 Target:5′-CCCCAATAAACCTTGAACAGTGACTAC-3′ (SEQ ID NO: 6737)5′-CAAUAAACCUUGAACAGUGACUAct-3′ (SEQ ID NO: 2710)3′-GGGUUAUUUGGAACUUGUCACUGAUGA-5′ (SEQ ID NO: 4724) LDHA-1842 Target:5′-CCCAATAAACCTTGAACAGTGACTACT-3′ (SEQ ID NO: 6738)5′-AAUAAACCUUGAACAGUGACUACtt-3′ (SEQ ID NO: 2711)3′-GGUUAUUUGGAACUUGUCACUGAUGAA-5′ (SEQ ID NO: 4725) LDHA-1843 Target:5′-CCAATAAACCTTGAACAGTGACTACTT-3′ (SEQ ID NO: 6739)5′-AUAAACCUUGAACAGUGACUACUtt-3′ (SEQ ID NO: 2712)3′-GUUAUUUGGAACUUGUCACUGAUGAAA-5′ (SEQ ID NO: 4726) LDHA-1844 Target:5′-CAATAAACCTTGAACAGTGACTACTTT-3′ (SEQ ID NO: 6740)5′-UAAACCUUGAACAGUGACUACUUtg-3′ (SEQ ID NO: 2713)3′-UUAUUUGGAACUUGUCACUGAUGAAAC-5′ (SEQ ID NO: 4727) LDHA-1845 Target:5′-AATAAACCTTGAACAGTGACTACTTTG-3′ (SEQ ID NO: 6741)5′-AAACCUUGAACAGUGACUACUUUgg-3′ (SEQ ID NO: 2714)3′-UAUUUGGAACUUGUCACUGAUGAAACC-5′ (SEQ ID NO: 4728) LDHA-1846 Target:5′-ATAAACCTTGAACAGTGACTACTTTGG-3′ (SEQ ID NO: 6742)5′-AACCUUGAACAGUGACUACUUUGgt-3′ (SEQ ID NO: 2715)3′-AUUUGGAACUUGUCACUGAUGAAACCA-5′ (SEQ ID NO: 4729) LDHA-1847 Target:5′-TAAACCTTGAACAGTGACTACTTTGGT-3′ (SEQ ID NO: 6743)5′-ACCUUGAACAGUGACUACUUUGGtt-3′ (SEQ ID NO: 2716)3′-UUUGGAACUUGUCACUGAUGAAACCAA-5′ (SEQ ID NO: 4730) LDHA-1848 Target:5′-AAACCTTGAACAGTGACTACTTTGGTT-3′ (SEQ ID NO: 6744)5′-CCUUGAACAGUGACUACUUUGGUta-3′ (SEQ ID NO: 2717)3′-UUGGAACUUGUCACUGAUGAAACCAAU-5′ (SEQ ID NO: 4731) LDHA-1849 Target:5′-AACCTTGAACAGTGACTACTTTGGTTA-3′ (SEQ ID NO: 6745)5′-CUUGAACAGUGACUACUUUGGUUaa-3′ (SEQ ID NO: 2718)3′-UGGAACUUGUCACUGAUGAAACCAAUU-5′ (SEQ ID NO: 4732) LDHA-1850 Target:5′-ACCTTGAACAGTGACTACTTTGGTTAA-3′ (SEQ ID NO: 6746)5′-UUGAACAGUGACUACUUUGGUUAat-3′ (SEQ ID NO: 2719)3′-GGAACUUGUCACUGAUGAAACCAAUUA-5′ (SEQ ID NO: 4733) LDHA-1851 Target:5′-CCTTGAACAGTGACTACTTTGGTTAAT-3′ (SEQ ID NO: 6747)5′-UGAACAGUGACUACUUUGGUUAAtt-3′ (SEQ ID NO: 2720)3′-GAACUUGUCACUGAUGAAACCAAUUAA-5′ (SEQ ID NO: 4734) LDHA-1852 Target:5′-CTTGAACAGTGACTACTTTGGTTAATT-3′ (SEQ ID NO: 6748)5′-GAACAGUGACUACUUUGGUUAAUtc-3′ (SEQ ID NO: 2721)3′-AACUUGUCACUGAUGAAACCAAUUAAG-5′ (SEQ ID NO: 4735) LDHA-1853 Target:5′-TTGAACAGTGACTACTTTGGTTAATTC-3′ (SEQ ID NO: 6749)5′-AACAGUGACUACUUUGGUUAAUUca-3′ (SEQ ID NO: 2722)3′-ACUUGUCACUGAUGAAACCAAUUAAGU-5′ (SEQ ID NO: 4736) LDHA-1854 Target:5′-TGAACAGTGACTACTTTGGTTAATTCA-3′ (SEQ ID NO: 6750)5′-ACAGUGACUACUUUGGUUAAUUCat-3′ (SEQ ID NO: 2723)3′-CUUGUCACUGAUGAAACCAAUUAAGUA-5′ (SEQ ID NO: 4737) LDHA-1855 Target:5′-GAACAGTGACTACTTTGGTTAATTCAT-3′ (SEQ ID NO: 6751)5′-CAGUGACUACUUUGGUUAAUUCAtt-3′ (SEQ ID NO: 2724)3′-UUGUCACUGAUGAAACCAAUUAAGUAA-5′ (SEQ ID NO: 4738) LDHA-1856 Target:5′-AACAGTGACTACTTTGGTTAATTCATT-3′ (SEQ ID NO: 6752)5′-AGUGACUACUUUGGUUAAUUCAUta-3′ (SEQ ID NO: 2725)3′-UGUCACUGAUGAAACCAAUUAAGUAAU-5′ (SEQ ID NO: 4739) LDHA-1857 Target:5′-ACAGTGACTACTTTGGTTAATTCATTA-3′ (SEQ ID NO: 6753)5′-GUGACUACUUUGGUUAAUUCAUUat-3′ (SEQ ID NO: 2726)3′-GUCACUGAUGAAACCAAUUAAGUAAUA-5′ (SEQ ID NO: 4740) LDHA-1858 Target:5′-CAGTGACTACTTTGGTTAATTCATTAT-3′ (SEQ ID NO: 6754)5′-UGACUACUUUGGUUAAUUCAUUAta-3′ (SEQ ID NO: 2727)3′-UCACUGAUGAAACCAAUUAAGUAAUAU-5′ (SEQ ID NO: 4741) LDHA-1859 Target:5′-AGTGACTACTTTGGTTAATTCATTATA-3′ (SEQ ID NO: 6755)5′-GACUACUUUGGUUAAUUCAUUAUat-3′ (SEQ ID NO: 2728)3′-CACUGAUGAAACCAAUUAAGUAAUAUA-5′ (SEQ ID NO: 4742) LDHA-1860 Target:5′-GTGACTACTTTGGTTAATTCATTATAT-3′ (SEQ ID NO: 6756)5′-ACUACUUUGGUUAAUUCAUUAUAtt-3′ (SEQ ID NO: 2729)3′-ACUGAUGAAACCAAUUAAGUAAUAUAA-5′ (SEQ ID NO: 4743) LDHA-1861 Target:5′-TGACTACTTTGGTTAATTCATTATATT-3′ (SEQ ID NO: 6757)5′-CUACUUUGGUUAAUUCAUUAUAUta-3′ (SEQ ID NO: 2730)3′-CUGAUGAAACCAAUUAAGUAAUAUAAU-5′ (SEQ ID NO: 4744) LDHA-1862 Target:5′-GACTACTTTGGTTAATTCATTATATTA-3′ (SEQ ID NO: 6758)5′-UACUUUGGUUAAUUCAUUAUAUUaa-3′ (SEQ ID NO: 2731)3′-UGAUGAAACCAAUUAAGUAAUAUAAUU-5′ (SEQ ID NO: 4745) LDHA-1863 Target:5′-ACTACTTTGGTTAATTCATTATATTAA-3′ (SEQ ID NO: 6759)5′-ACUUUGGUUAAUUCAUUAUAUUAag-3′ (SEQ ID NO: 2732)3′-GAUGAAACCAAUUAAGUAAUAUAAUUC-5′ (SEQ ID NO: 4746) LDHA-1864 Target:5′-CTACTTTGGTTAATTCATTATATTAAG-3′ (SEQ ID NO: 6760)5′-CUUUGGUUAAUUCAUUAUAUUAAga-3′ (SEQ ID NO: 2733)3′-AUGAAACCAAUUAAGUAAUAUAAUUCU-5′ (SEQ ID NO: 4747) LDHA-1865 Target:5′-TACTTTGGTTAATTCATTATATTAAGA-3′ (SEQ ID NO: 6761)5′-UUUGGUUAAUUCAUUAUAUUAAGat-3′ (SEQ ID NO: 2734)3′-UGAAACCAAUUAAGUAAUAUAAUUCUA-5′ (SEQ ID NO: 4748) LDHA-1866 Target:5′-ACTTTGGTTAATTCATTATATTAAGAT-3′ (SEQ ID NO: 6762)5′-UUGGUUAAUUCAUUAUAUUAAGAta-3′ (SEQ ID NO: 2735)3′-GAAACCAAUUAAGUAAUAUAAUUCUAU-5′ (SEQ ID NO: 4749) LDHA-1867 Target:5′-CTTTGGTTAATTCATTATATTAAGATA-3′ (SEQ ID NO: 6763)5′-UGGUUAAUUCAUUAUAUUAAGAUat-3′ (SEQ ID NO: 2736)3′-AAACCAAUUAAGUAAUAUAAUUCUAUA-5′ (SEQ ID NO: 4750) LDHA-1868 Target:5′-TTTGGTTAATTCATTATATTAAGATAT-3′ (SEQ ID NO: 6764)5′-GGUUAAUUCAUUAUAUUAAGAUAta-3′ (SEQ ID NO: 2737)3′-AACCAAUUAAGUAAUAUAAUUCUAUAU-5′ (SEQ ID NO: 4751) LDHA-1869 Target:5′-TTGGTTAATTCATTATATTAAGATATA-3′ (SEQ ID NO: 6765)5′-GUUAAUUCAUUAUAUUAAGAUAUaa-3′ (SEQ ID NO: 2738)3′-ACCAAUUAAGUAAUAUAAUUCUAUAUU-5′ (SEQ ID NO: 4752) LDHA-1870 Target:5′-TGGTTAATTCATTATATTAAGATATAA-3′ (SEQ ID NO: 6766)5′-UUAAUUCAUUAUAUUAAGAUAUAaa-3′ (SEQ ID NO: 2739)3′-CCAAUUAAGUAAUAUAAUUCUAUAUUU-5′ (SEQ ID NO: 4753) LDHA-1871 Target:5′-GGTTAATTCATTATATTAAGATATAAA-3′ (SEQ ID NO: 6767)5′-UAAUUCAUUAUAUUAAGAUAUAAag-3′ (SEQ ID NO: 2740)3′-CAAUUAAGUAAUAUAAUUCUAUAUUUC-5′ (SEQ ID NO: 4754) LDHA-1872 Target:5′-GTTAATTCATTATATTAAGATATAAAG-3′ (SEQ ID NO: 6768)5′-AAUUCAUUAUAUUAAGAUAUAAAgt-3′ (SEQ ID NO: 2741)3′-AAUUAAGUAAUAUAAUUCUAUAUUUCA-5′ (SEQ ID NO: 4755) LDHA-1873 Target:5′-TTAATTCATTATATTAAGATATAAAGT-3′ (SEQ ID NO: 6769)5′-AUUCAUUAUAUUAAGAUAUAAAGtc-3′ (SEQ ID NO: 2742)3′-AUUAAGUAAUAUAAUUCUAUAUUUCAG-5′ (SEQ ID NO: 4756) LDHA-1874 Target:5′-TAATTCATTATATTAAGATATAAAGTC-3′ (SEQ ID NO: 6770)5′-UUCAUUAUAUUAAGAUAUAAAGUca-3′ (SEQ ID NO: 2743)3′-UUAAGUAAUAUAAUUCUAUAUUUCAGU-5′ (SEQ ID NO: 4757) LDHA-1875 Target:5′-AATTCATTATATTAAGATATAAAGTCA-3′ (SEQ ID NO: 6771)5′-UCAUUAUAUUAAGAUAUAAAGUCat-3′ (SEQ ID NO: 2744)3′-UAAGUAAUAUAAUUCUAUAUUUCAGUA-5′ (SEQ ID NO: 4758) LDHA-1876 Target:5′-ATTCATTATATTAAGATATAAAGTCAT-3′ (SEQ ID NO: 6772)5′-CAUUAUAUUAAGAUAUAAAGUCAta-3′ (SEQ ID NO: 2745)3′-AAGUAAUAUAAUUCUAUAUUUCAGUAU-5′ (SEQ ID NO: 4759) LDHA-1877 Target:5′-TTCATTATATTAAGATATAAAGTCATA-3′ (SEQ ID NO: 6773)5′-AUUAUAUUAAGAUAUAAAGUCAUaa-3′ (SEQ ID NO: 2746)3′-AGUAAUAUAAUUCUAUAUUUCAGUAUU-5′ (SEQ ID NO: 4760) LDHA-1878 Target:5′-TCATTATATTAAGATATAAAGTCATAA-3′ (SEQ ID NO: 6774)5′-UUAUAUUAAGAUAUAAAGUCAUAaa-3′ (SEQ ID NO: 2747)3′-GUAAUAUAAUUCUAUAUUUCAGUAUUU-5′ (SEQ ID NO: 4761) LDHA-1879 Target:5′-CATTATATTAAGATATAAAGTCATAAA-3′ (SEQ ID NO: 6775)5′-UAUAUUAAGAUAUAAAGUCAUAAag-3′ (SEQ ID NO: 2748)3′-UAAUAUAAUUCUAUAUUUCAGUAUUUC-5′ (SEQ ID NO: 4762) LDHA-1880 Target:5′-ATTATATTAAGATATAAAGTCATAAAG-3′ (SEQ ID NO: 6776)5′-AUAUUAAGAUAUAAAGUCAUAAAgc-3′ (SEQ ID NO: 2749)3′-AAUAUAAUUCUAUAUUUCAGUAUUUCG-5′ (SEQ ID NO: 4763) LDHA-1881 Target:5′-TTATATTAAGATATAAAGTCATAAAGC-3′ (SEQ ID NO: 6777)5′-UAUUAAGAUAUAAAGUCAUAAAGct-3′ (SEQ ID NO: 2750)3′-AUAUAAUUCUAUAUUUCAGUAUUUCGA-5′ (SEQ ID NO: 4764) LDHA-1882 Target:5′-TATATTAAGATATAAAGTCATAAAGCT-3′ (SEQ ID NO: 6778)5′-AUUAAGAUAUAAAGUCAUAAAGCtg-3′ (SEQ ID NO: 2751)3′-UAUAAUUCUAUAUUUCAGUAUUUCGAC-5′ (SEQ ID NO: 4765) LDHA-1883 Target:5′-ATATTAAGATATAAAGTCATAAAGCTG-3′ (SEQ ID NO: 6779)5′-UUAAGAUAUAAAGUCAUAAAGCUgc-3′ (SEQ ID NO: 2752)3′-AUAAUUCUAUAUUUCAGUAUUUCGACG-5′ (SEQ ID NO: 4766) LDHA-1884 Target:5′-TATTAAGATATAAAGTCATAAAGCTGC-3′ (SEQ ID NO: 6780)5′-UAAGAUAUAAAGUCAUAAAGCUGct-3′ (SEQ ID NO: 2753)3′-UAAUUCUAUAUUUCAGUAUUUCGACGA-5′ (SEQ ID NO: 4767) LDHA-1885 Target:5′-ATTAAGATATAAAGTCATAAAGCTGCT-3′ (SEQ ID NO: 6781)5′-AAGAUAUAAAGUCAUAAAGCUGCta-3′ (SEQ ID NO: 2754)3′-AAUUCUAUAUUUCAGUAUUUCGACGAU-5′ (SEQ ID NO: 4768) LDHA-1886 Target:5′-TTAAGATATAAAGTCATAAAGCTGCTA-3′ (SEQ ID NO: 6782)5′-AGAUAUAAAGUCAUAAAGCUGCUag-3′ (SEQ ID NO: 2755)3′-AUUCUAUAUUUCAGUAUUUCGACGAUC-5′ (SEQ ID NO: 4769) LDHA-1887 Target:5′-TAAGATATAAAGTCATAAAGCTGCTAG-3′ (SEQ ID NO: 6783)5′-GAUAUAAAGUCAUAAAGCUGCUAgt-3′ (SEQ ID NO: 2756)3′-UUCUAUAUUUCAGUAUUUCGACGAUCA-5′ (SEQ ID NO: 4770) LDHA-1888 Target:5′-AAGATATAAAGTCATAAAGCTGCTAGT-3′ (SEQ ID NO: 6784)5′-AUAUAAAGUCAUAAAGCUGCUAGtt-3′ (SEQ ID NO: 2757)3′-UCUAUAUUUCAGUAUUUCGACGAUCAA-5′ (SEQ ID NO: 4771) LDHA-1889 Target:5′-AGATATAAAGTCATAAAGCTGCTAGTT-3′ (SEQ ID NO: 6785)5′-UAUAAAGUCAUAAAGCUGCUAGUta-3′ (SEQ ID NO: 2758)3′-CUAUAUUUCAGUAUUUCGACGAUCAAU-5′ (SEQ ID NO: 4772) LDHA-1890 Target:5′-GATATAAAGTCATAAAGCTGCTAGTTA-3′ (SEQ ID NO: 6786)5′-AUAAAGUCAUAAAGCUGCUAGUUat-3′ (SEQ ID NO: 2759)3′-UAUAUUUCAGUAUUUCGACGAUCAAUA-5′ (SEQ ID NO: 4773) LDHA-1891 Target:5′-ATATAAAGTCATAAAGCTGCTAGTTAT-3′ (SEQ ID NO: 6787)5′-UAAAGUCAUAAAGCUGCUAGUUAtt-3′ (SEQ ID NO: 2760)3′-AUAUUUCAGUAUUUCGACGAUCAAUAA-5′ (SEQ ID NO: 4774) LDHA-1892 Target:5′-TATAAAGTCATAAAGCTGCTAGTTATT-3′ (SEQ ID NO: 6788)5′-AAAGUCAUAAAGCUGCUAGUUAUta-3′ (SEQ ID NO: 2761)3′-UAUUUCAGUAUUUCGACGAUCAAUAAU-5′ (SEQ ID NO: 4775) LDHA-1893 Target:5′-ATAAAGTCATAAAGCTGCTAGTTATTA-3′ (SEQ ID NO: 6789)5′-AAGUCAUAAAGCUGCUAGUUAUUat-3′ (SEQ ID NO: 2762)3′-AUUUCAGUAUUUCGACGAUCAAUAAUA-5′ (SEQ ID NO: 4776) LDHA-1894 Target:5′-TAAAGTCATAAAGCTGCTAGTTATTAT-3′ (SEQ ID NO: 6790)5′-AGUCAUAAAGCUGCUAGUUAUUAta-3′ (SEQ ID NO: 2763)3′-UUUCAGUAUUUCGACGAUCAAUAAUAU-5′ (SEQ ID NO: 4777) LDHA-1895 Target:5′-AAAGTCATAAAGCTGCTAGTTATTATA-3′ (SEQ ID NO: 6791)5′-GUCAUAAAGCUGCUAGUUAUUAUat-3′ (SEQ ID NO: 2764)3′-UUCAGUAUUUCGACGAUCAAUAAUAUA-5′ (SEQ ID NO: 4778) LDHA-1896 Target:5′-AAGTCATAAAGCTGCTAGTTATTATAT-3′ (SEQ ID NO: 6792)5′-UCAUAAAGCUGCUAGUUAUUAUAtt-3′ (SEQ ID NO: 2765)3′-UCAGUAUUUCGACGAUCAAUAAUAUAA-5′ (SEQ ID NO: 4779) LDHA-1897 Target:5′-AGTCATAAAGCTGCTAGTTATTATATT-3′ (SEQ ID NO: 6793)5′-CAUAAAGCUGCUAGUUAUUAUAUta-3′ (SEQ ID NO: 2766)3′-CAGUAUUUCGACGAUCAAUAAUAUAAU-5′ (SEQ ID NO: 4780) LDHA-1898 Target:5′-GTCATAAAGCTGCTAGTTATTATATTA-3′ (SEQ ID NO: 6794)5′-AUAAAGCUGCUAGUUAUUAUAUUaa-3′ (SEQ ID NO: 2767)3′-AGUAUUUCGACGAUCAAUAAUAUAAUU-5′ (SEQ ID NO: 4781) LDHA-1899 Target:5′-TCATAAAGCTGCTAGTTATTATATTAA-3′ (SEQ ID NO: 6795)5′-UAAAGCUGCUAGUUAUUAUAUUAat-3′ (SEQ ID NO: 2768)3′-GUAUUUCGACGAUCAAUAAUAUAAUUA-5′ (SEQ ID NO: 4782) LDHA-1900 Target:5′-CATAAAGCTGCTAGTTATTATATTAAT-3′ (SEQ ID NO: 6796)5′-AAAGCUGCUAGUUAUUAUAUUAAtt-3′ (SEQ ID NO: 2769)3′-UAUUUCGACGAUCAAUAAUAUAAUUAA-5′ (SEQ ID NO: 4783) LDHA-1901 Target:5′-ATAAAGCTGCTAGTTATTATATTAATT-3′ (SEQ ID NO: 6797)5′-AAGCUGCUAGUUAUUAUAUUAAUtt-3′ (SEQ ID NO: 2770)3′-AUUUCGACGAUCAAUAAUAUAAUUAAA-5′ (SEQ ID NO: 4784) LDHA-1902 Target:5′-TAAAGCTGCTAGTTATTATATTAATTT-3′ (SEQ ID NO: 6798)5′-AGCUGCUAGUUAUUAUAUUAAUUtg-3′ (SEQ ID NO: 2771)3′-UUUCGACGAUCAAUAAUAUAAUUAAAC-5′ (SEQ ID NO: 4785) LDHA-1903 Target:5′-AAAGCTGCTAGTTATTATATTAATTTG-3′ (SEQ ID NO: 6799)5′-GCUGCUAGUUAUUAUAUUAAUUUgg-3′ (SEQ ID NO: 2772)3′-UUCGACGAUCAAUAAUAUAAUUAAACC-5′ (SEQ ID NO: 4786) LDHA-1904 Target:5′-AAGCTGCTAGTTATTATATTAATTTGG-3′ (SEQ ID NO: 6800)5′-CUGCUAGUUAUUAUAUUAAUUUGga-3′ (SEQ ID NO: 2773)3′-UCGACGAUCAAUAAUAUAAUUAAACCU-5′ (SEQ ID NO: 4787) LDHA-1905 Target:5′-AGCTGCTAGTTATTATATTAATTTGGA-3′ (SEQ ID NO: 6801)5′-UGCUAGUUAUUAUAUUAAUUUGGaa-3′ (SEQ ID NO: 2774)3′-CGACGAUCAAUAAUAUAAUUAAACCUU-5′ (SEQ ID NO: 4788) LDHA-1906 Target:5′-GCTGCTAGTTATTATATTAATTTGGAA-3′ (SEQ ID NO: 6802)5′-GCUAGUUAUUAUAUUAAUUUGGAaa-3′ (SEQ ID NO: 2775)3′-GACGAUCAAUAAUAUAAUUAAACCUUU-5′ (SEQ ID NO: 4789) LDHA-1907 Target:5′-CTGCTAGTTATTATATTAATTTGGAAA-3′ (SEQ ID NO: 6803)5′-CUAGUUAUUAUAUUAAUUUGGAAat-3′ (SEQ ID NO: 2776)3′-ACGAUCAAUAAUAUAAUUAAACCUUUA-5′ (SEQ ID NO: 4790) LDHA-1908 Target:5′-TGCTAGTTATTATATTAATTTGGAAAT-3′ (SEQ ID NO: 6804)5′-UAGUUAUUAUAUUAAUUUGGAAAta-3′ (SEQ ID NO: 2777)3′-CGAUCAAUAAUAUAAUUAAACCUUUAU-5′ (SEQ ID NO: 4791) LDHA-1909 Target:5′-GCTAGTTATTATATTAATTTGGAAATA-3′ (SEQ ID NO: 6805)5′-AGUUAUUAUAUUAAUUUGGAAAUat-3′ (SEQ ID NO: 2778)3′-GAUCAAUAAUAUAAUUAAACCUUUAUA-5′ (SEQ ID NO: 4792) LDHA-1910 Target:5′-CTAGTTATTATATTAATTTGGAAATAT-3′ (SEQ ID NO: 6806)5′-GUUAUUAUAUUAAUUUGGAAAUAtt-3′ (SEQ ID NO: 2779)3′-AUCAAUAAUAUAAUUAAACCUUUAUAA-5′ (SEQ ID NO: 4793) LDHA-1911 Target:5′-TAGTTATTATATTAATTTGGAAATATT-3′ (SEQ ID NO: 6807)5′-UUAUUAUAUUAAUUUGGAAAUAUta-3′ (SEQ ID NO: 2780)3′-UCAAUAAUAUAAUUAAACCUUUAUAAU-5′ (SEQ ID NO: 4794) LDHA-1912 Target:5′-AGTTATTATATTAATTTGGAAATATTA-3′ (SEQ ID NO: 6808)5′-UAUUAUAUUAAUUUGGAAAUAUUag-3′ (SEQ ID NO: 2781)3′-CAAUAAUAUAAUUAAACCUUUAUAAUC-5′ (SEQ ID NO: 4795) LDHA-1913 Target:5′-GTTATTATATTAATTTGGAAATATTAG-3′ (SEQ ID NO: 6809)5′-AUUAUAUUAAUUUGGAAAUAUUAgg-3′ (SEQ ID NO: 2782)3′-AAUAAUAUAAUUAAACCUUUAUAAUCC-5′ (SEQ ID NO: 4796) LDHA-1914 Target:5′-TTATTATATTAATTTGGAAATATTAGG-3′ (SEQ ID NO: 6810)5′-UUAUAUUAAUUUGGAAAUAUUAGgc-3′ (SEQ ID NO: 2783)3′-AUAAUAUAAUUAAACCUUUAUAAUCCG-5′ (SEQ ID NO: 4797) LDHA-1915 Target:5′-TATTATATTAATTTGGAAATATTAGGC-3′ (SEQ ID NO: 6811)5′-UAUAUUAAUUUGGAAAUAUUAGGct-3′ (SEQ ID NO: 2784)3′-UAAUAUAAUUAAACCUUUAUAAUCCGA-5′ (SEQ ID NO: 4798) LDHA-1916 Target:5′-ATTATATTAATTTGGAAATATTAGGCT-3′ (SEQ ID NO: 6812)5′-AUAUUAAUUUGGAAAUAUUAGGCta-3′ (SEQ ID NO: 2785)3′-AAUAUAAUUAAACCUUUAUAAUCCGAU-5′ (SEQ ID NO: 4799) LDHA-1917 Target:5′-TTATATTAATTTGGAAATATTAGGCTA-3′ (SEQ ID NO: 6813)5′-UAUUAAUUUGGAAAUAUUAGGCUat-3′ (SEQ ID NO: 2786)3′-AUAUAAUUAAACCUUUAUAAUCCGAUA-5′ (SEQ ID NO: 4800) LDHA-1918 Target:5′-TATATTAATTTGGAAATATTAGGCTAT-3′ (SEQ ID NO: 6814)5′-AUUAAUUUGGAAAUAUUAGGCUAtt-3′ (SEQ ID NO: 2787)3′-UAUAAUUAAACCUUUAUAAUCCGAUAA-5′ (SEQ ID NO: 4801) LDHA-1919 Target:5′-ATATTAATTTGGAAATATTAGGCTATT-3′ (SEQ ID NO: 6815)5′-UUAAUUUGGAAAUAUUAGGCUAUtc-3′ (SEQ ID NO: 2788)3′-AUAAUUAAACCUUUAUAAUCCGAUAAG-5′ (SEQ ID NO: 4802) LDHA-1920 Target:5′-TATTAATTTGGAAATATTAGGCTATTC-3′ (SEQ ID NO: 6816)5′-UAAUUUGGAAAUAUUAGGCUAUUct-3′ (SEQ ID NO: 2789)3′-UAAUUAAACCUUUAUAAUCCGAUAAGA-5′ (SEQ ID NO: 4803) LDHA-1921 Target:5′-ATTAATTTGGAAATATTAGGCTATTCT-3′ (SEQ ID NO: 6817)5′-AAUUUGGAAAUAUUAGGCUAUUCtt-3′ (SEQ ID NO: 2790)3′-AAUUAAACCUUUAUAAUCCGAUAAGAA-5′ (SEQ ID NO: 4804) LDHA-1922 Target:5′-TTAATTTGGAAATATTAGGCTATTCTT-3′ (SEQ ID NO: 6818)5′-AUUUGGAAAUAUUAGGCUAUUCUtg-3′ (SEQ ID NO: 2791)3′-AUUAAACCUUUAUAAUCCGAUAAGAAC-5′ (SEQ ID NO: 4805) LDHA-1923 Target:5′-TAATTTGGAAATATTAGGCTATTCTTG-3′ (SEQ ID NO: 6819)5′-UUUGGAAAUAUUAGGCUAUUCUUgg-3′ (SEQ ID NO: 2792)3′-UUAAACCUUUAUAAUCCGAUAAGAACC-5′ (SEQ ID NO: 4806) LDHA-1924 Target:5′-AATTTGGAAATATTAGGCTATTCTTGG-3′ (SEQ ID NO: 6820)5′-UUGGAAAUAUUAGGCUAUUCUUGgg-3′ (SEQ ID NO: 2793)3′-UAAACCUUUAUAAUCCGAUAAGAACCC-5′ (SEQ ID NO: 4807) LDHA-1925 Target:5′-ATTTGGAAATATTAGGCTATTCTTGGG-3′ (SEQ ID NO: 6821)5′-UGGAAAUAUUAGGCUAUUCUUGGgc-3′ (SEQ ID NO: 2794)3′-AAACCUUUAUAAUCCGAUAAGAACCCG-5′ (SEQ ID NO: 4808) LDHA-1926 Target:5′-TTTGGAAATATTAGGCTATTCTTGGGC-3′ (SEQ ID NO: 6822)5′-GGAAAUAUUAGGCUAUUCUUGGGca-3′ (SEQ ID NO: 2795)3′-AACCUUUAUAAUCCGAUAAGAACCCGU-5′ (SEQ ID NO: 4809) LDHA-1927 Target:5′-TTGGAAATATTAGGCTATTCTTGGGCA-3′ (SEQ ID NO: 6823)5′-GAAAUAUUAGGCUAUUCUUGGGCaa-3′ (SEQ ID NO: 2796)3′-ACCUUUAUAAUCCGAUAAGAACCCGUU-5′ (SEQ ID NO: 4810) LDHA-1928 Target:5′-TGGAAATATTAGGCTATTCTTGGGCAA-3′ (SEQ ID NO: 6824)5′-AAAUAUUAGGCUAUUCUUGGGCAac-3′ (SEQ ID NO: 2797)3′-CCUUUAUAAUCCGAUAAGAACCCGUUG-5′ (SEQ ID NO: 4811) LDHA-1929 Target:5′-GGAAATATTAGGCTATTCTTGGGCAAC-3′ (SEQ ID NO: 6825)5′-AAUAUUAGGCUAUUCUUGGGCAAcc-3′ (SEQ ID NO: 2798)3′-CUUUAUAAUCCGAUAAGAACCCGUUGG-5′ (SEQ ID NO: 4812) LDHA-1930 Target:5′-GAAATATTAGGCTATTCTTGGGCAACC-3′ (SEQ ID NO: 6826)5′-AUAUUAGGCUAUUCUUGGGCAACcc-3′ (SEQ ID NO: 2799)3′-UUUAUAAUCCGAUAAGAACCCGUUGGG-5′ (SEQ ID NO: 4813) LDHA-1931 Target:5′-AAATATTAGGCTATTCTTGGGCAACCC-3′ (SEQ ID NO: 6827)5′-UAUUAGGCUAUUCUUGGGCAACCct-3′ (SEQ ID NO: 2800)3′-UUAUAAUCCGAUAAGAACCCGUUGGGA-5′ (SEQ ID NO: 4814) LDHA-1932 Target:5′-AATATTAGGCTATTCTTGGGCAACCCT-3′ (SEQ ID NO: 6828)5′-AUUAGGCUAUUCUUGGGCAACCCtg-3′ (SEQ ID NO: 2801)3′-UAUAAUCCGAUAAGAACCCGUUGGGAC-5′ (SEQ ID NO: 4815) LDHA-1933 Target:5′-ATATTAGGCTATTCTTGGGCAACCCTG-3′ (SEQ ID NO: 6829)5′-UUAGGCUAUUCUUGGGCAACCCUgc-3′ (SEQ ID NO: 2802)3′-AUAAUCCGAUAAGAACCCGUUGGGACG-5′ (SEQ ID NO: 4816) LDHA-1934 Target:5′-TATTAGGCTATTCTTGGGCAACCCTGC-3′ (SEQ ID NO: 6830)5′-UAGGCUAUUCUUGGGCAACCCUGca-3′ (SEQ ID NO: 2803)3′-UAAUCCGAUAAGAACCCGUUGGGACGU-5′ (SEQ ID NO: 4817) LDHA-1935 Target:5′-ATTAGGCTATTCTTGGGCAACCCTGCA-3′ (SEQ ID NO: 6831)5′-AGGCUAUUCUUGGGCAACCCUGCaa-3′ (SEQ ID NO: 2804)3′-AAUCCGAUAAGAACCCGUUGGGACGUU-5′ (SEQ ID NO: 4818) LDHA-1936 Target:5′-TTAGGCTATTCTTGGGCAACCCTGCAA-3′ (SEQ ID NO: 6832)5′-GGCUAUUCUUGGGCAACCCUGCAac-3′ (SEQ ID NO: 2805)3′-AUCCGAUAAGAACCCGUUGGGACGUUG-5′ (SEQ ID NO: 4819) LDHA-1937 Target:5′-TAGGCTATTCTTGGGCAACCCTGCAAC-3′ (SEQ ID NO: 6833)5′-GCUAUUCUUGGGCAACCCUGCAAcg-3′ (SEQ ID NO: 2806)3′-UCCGAUAAGAACCCGUUGGGACGUUGC-5′ (SEQ ID NO: 4820) LDHA-1938 Target:5′-AGGCTATTCTTGGGCAACCCTGCAACG-3′ (SEQ ID NO: 6834)5′-CUAUUCUUGGGCAACCCUGCAACga-3′ (SEQ ID NO: 2807)3′-CCGAUAAGAACCCGUUGGGACGUUGCU-5′ (SEQ ID NO: 4821) LDHA-1939 Target:5′-GGCTATTCTTGGGCAACCCTGCAACGA-3′ (SEQ ID NO: 6835)5′-UAUUCUUGGGCAACCCUGCAACGat-3′ (SEQ ID NO: 2808)3′-CGAUAAGAACCCGUUGGGACGUUGCUA-5′ (SEQ ID NO: 4822) LDHA-1940 Target:5′-GCTATTCTTGGGCAACCCTGCAACGAT-3′ (SEQ ID NO: 6836)5′-AUUCUUGGGCAACCCUGCAACGAtt-3′ (SEQ ID NO: 2809)3′-GAUAAGAACCCGUUGGGACGUUGCUAA-5′ (SEQ ID NO: 4823) LDHA-1941 Target:5′-CTATTCTTGGGCAACCCTGCAACGATT-3′ (SEQ ID NO: 6837)5′-UUCUUGGGCAACCCUGCAACGAUtt-3′ (SEQ ID NO: 2810)3′-AUAAGAACCCGUUGGGACGUUGCUAAA-5′ (SEQ ID NO: 4824) LDHA-1942 Target:5′-TATTCTTGGGCAACCCTGCAACGATTT-3′ (SEQ ID NO: 6838)5′-UCUUGGGCAACCCUGCAACGAUUtt-3′ (SEQ ID NO: 2811)3′-UAAGAACCCGUUGGGACGUUGCUAAAA-5′ (SEQ ID NO: 4825) LDHA-1943 Target:5′-ATTCTTGGGCAACCCTGCAACGATTTT-3′ (SEQ ID NO: 6839)5′-CUUGGGCAACCCUGCAACGAUUUtt-3′ (SEQ ID NO: 2812)3′-AAGAACCCGUUGGGACGUUGCUAAAAA-5′ (SEQ ID NO: 4826) LDHA-1944 Target:5′-TTCTTGGGCAACCCTGCAACGATTTTT-3′ (SEQ ID NO: 6840)5′-UUGGGCAACCCUGCAACGAUUUUtt-3′ (SEQ ID NO: 2813)3′-AGAACCCGUUGGGACGUUGCUAAAAAA-5′ (SEQ ID NO: 4827) LDHA-1945 Target:5′-TCTTGGGCAACCCTGCAACGATTTTTT-3′ (SEQ ID NO: 6841)5′-UGGGCAACCCUGCAACGAUUUUUtc-3′ (SEQ ID NO: 2814)3′-GAACCCGUUGGGACGUUGCUAAAAAAG-5′ (SEQ ID NO: 4828) LDHA-1946 Target:5′-CTTGGGCAACCCTGCAACGATTTTTTC-3′ (SEQ ID NO: 6842)5′-GGGCAACCCUGCAACGAUUUUUUct-3′ (SEQ ID NO: 2815)3′-AACCCGUUGGGACGUUGCUAAAAAAGA-5′ (SEQ ID NO: 4829) LDHA-1947 Target:5′-TTGGGCAACCCTGCAACGATTTTTTCT-3′ (SEQ ID NO: 6843)5′-GGCAACCCUGCAACGAUUUUUUCta-3′ (SEQ ID NO: 2816)3′-ACCCGUUGGGACGUUGCUAAAAAAGAU-5′ (SEQ ID NO: 4830) LDHA-1948 Target:5′-TGGGCAACCCTGCAACGATTTTTTCTA-3′ (SEQ ID NO: 6844)5′-GCAACCCUGCAACGAUUUUUUCUaa-3′ (SEQ ID NO: 2817)3′-CCCGUUGGGACGUUGCUAAAAAAGAUU-5′ (SEQ ID NO: 4831) LDHA-1949 Target:5′-GGGCAACCCTGCAACGATTTTTTCTAA-3′ (SEQ ID NO: 6845)5′-CAACCCUGCAACGAUUUUUUCUAac-3′ (SEQ ID NO: 2818)3′-CCGUUGGGACGUUGCUAAAAAAGAUUG-5′ (SEQ ID NO: 4832) LDHA-1950 Target:5′-GGCAACCCTGCAACGATTTTTTCTAAC-3′ (SEQ ID NO: 6846)5′-AACCCUGCAACGAUUUUUUCUAAca-3′ (SEQ ID NO: 2819)3′-CGUUGGGACGUUGCUAAAAAAGAUUGU-5′ (SEQ ID NO: 4833) LDHA-1951 Target:5′-GCAACCCTGCAACGATTTTTTCTAACA-3′ (SEQ ID NO: 6847)5′-ACCCUGCAACGAUUUUUUCUAACag-3′ (SEQ ID NO: 2820)3′-GUUGGGACGUUGCUAAAAAAGAUUGUC-5′ (SEQ ID NO: 4834) LDHA-1952 Target:5′-CAACCCTGCAACGATTTTTTCTAACAG-3′ (SEQ ID NO: 6848)5′-CCCUGCAACGAUUUUUUCUAACAgg-3′ (SEQ ID NO: 2821)3′-UUGGGACGUUGCUAAAAAAGAUUGUCC-5′ (SEQ ID NO: 4835) LDHA-1953 Target:5′-AACCCTGCAACGATTTTTTCTAACAGG-3′ (SEQ ID NO: 6849)5′-CCUGCAACGAUUUUUUCUAACAGgg-3′ (SEQ ID NO: 2822)3′-UGGGACGUUGCUAAAAAAGAUUGUCCC-5′ (SEQ ID NO: 4836) LDHA-1954 Target:5′-ACCCTGCAACGATTTTTTCTAACAGGG-3′ (SEQ ID NO: 6850)5′-CUGCAACGAUUUUUUCUAACAGGga-3′ (SEQ ID NO: 2823)3′-GGGACGUUGCUAAAAAAGAUUGUCCCU-5′ (SEQ ID NO: 4837) LDHA-1955 Target:5′-CCCTGCAACGATTTTTTCTAACAGGGA-3′ (SEQ ID NO: 6851)5′-UGCAACGAUUUUUUCUAACAGGGat-3′ (SEQ ID NO: 2824)3′-GGACGUUGCUAAAAAAGAUUGUCCCUA-5′ (SEQ ID NO: 4838) LDHA-1956 Target:5′-CCTGCAACGATTTTTTCTAACAGGGAT-3′ (SEQ ID NO: 6852)5′-GCAACGAUUUUUUCUAACAGGGAta-3′ (SEQ ID NO: 2825)3′-GACGUUGCUAAAAAAGAUUGUCCCUAU-5′ (SEQ ID NO: 4839) LDHA-1957 Target:5′-CTGCAACGATTTTTTCTAACAGGGATA-3′ (SEQ ID NO: 6853)5′-CAACGAUUUUUUCUAACAGGGAUat-3′ (SEQ ID NO: 2826)3′-ACGUUGCUAAAAAAGAUUGUCCCUAUA-5′ (SEQ ID NO: 4840) LDHA-1958 Target:5′-TGCAACGATTTTTTCTAACAGGGATAT-3′ (SEQ ID NO: 6854)5′-AACGAUUUUUUCUAACAGGGAUAtt-3′ (SEQ ID NO: 2827)3′-CGUUGCUAAAAAAGAUUGUCCCUAUAA-5′ (SEQ ID NO: 4841) LDHA-1959 Target:5′-GCAACGATTTTTTCTAACAGGGATATT-3′ (SEQ ID NO: 6855)5′-ACGAUUUUUUCUAACAGGGAUAUta-3′ (SEQ ID NO: 2828)3′-GUUGCUAAAAAAGAUUGUCCCUAUAAU-5′ (SEQ ID NO: 4842) LDHA-1960 Target:5′-CAACGATTTTTTCTAACAGGGATATTA-3′ (SEQ ID NO: 6856)5′-CGAUUUUUUCUAACAGGGAUAUUat-3′ (SEQ ID NO: 2829)3′-UUGCUAAAAAAGAUUGUCCCUAUAAUA-5′ (SEQ ID NO: 4843) LDHA-1961 Target:5′-AACGATTTTTTCTAACAGGGATATTAT-3′ (SEQ ID NO: 6857)5′-GAUUUUUUCUAACAGGGAUAUUAtt-3′ (SEQ ID NO: 2830)3′-UGCUAAAAAAGAUUGUCCCUAUAAUAA-5′ (SEQ ID NO: 4844) LDHA-1962 Target:5′-ACGATTTTTTCTAACAGGGATATTATT-3′ (SEQ ID NO: 6858)5′-AUUUUUUCUAACAGGGAUAUUAUtg-3′ (SEQ ID NO: 2831)3′-GCUAAAAAAGAUUGUCCCUAUAAUAAC-5′ (SEQ ID NO: 4845) LDHA-1963 Target:5′-CGATTTTTTCTAACAGGGATATTATTG-3′ (SEQ ID NO: 6859)5′-UUUUUUCUAACAGGGAUAUUAUUga-3′ (SEQ ID NO: 2832)3′-CUAAAAAAGAUUGUCCCUAUAAUAACU-5′ (SEQ ID NO: 4846) LDHA-1964 Target:5′-GATTTTTTCTAACAGGGATATTATTGA-3′ (SEQ ID NO: 6860)5′-UUUUUCUAACAGGGAUAUUAUUGac-3′ (SEQ ID NO: 2833)3′-UAAAAAAGAUUGUCCCUAUAAUAACUG-5′ (SEQ ID NO: 4847) LDHA-1965 Target:5′-ATTTTTTCTAACAGGGATATTATTGAC-3′ (SEQ ID NO: 6861)5′-UUUUCUAACAGGGAUAUUAUUGAct-3′ (SEQ ID NO: 2834)3′-AAAAAAGAUUGUCCCUAUAAUAACUGA-5′ (SEQ ID NO: 4848) LDHA-1966 Target:5′-TTTTTTCTAACAGGGATATTATTGACT-3′ (SEQ ID NO: 6862)5′-UUUCUAACAGGGAUAUUAUUGACta-3′ (SEQ ID NO: 2835)3′-AAAAAGAUUGUCCCUAUAAUAACUGAU-5′ (SEQ ID NO: 4849) LDHA-1967 Target:5′-TTTTTCTAACAGGGATATTATTGACTA-3′ (SEQ ID NO: 6863)5′-UUCUAACAGGGAUAUUAUUGACUaa-3′ (SEQ ID NO: 2836)3′-AAAAGAUUGUCCCUAUAAUAACUGAUU-5′ (SEQ ID NO: 4850) LDHA-1968 Target:5′-TTTTCTAACAGGGATATTATTGACTAA-3′ (SEQ ID NO: 6864)5′-UCUAACAGGGAUAUUAUUGACUAat-3′ (SEQ ID NO: 2837)3′-AAAGAUUGUCCCUAUAAUAACUGAUUA-5′ (SEQ ID NO: 4851) LDHA-1969 Target:5′-TTTCTAACAGGGATATTATTGACTAAT-3′ (SEQ ID NO: 6865)5′-CUAACAGGGAUAUUAUUGACUAAta-3′ (SEQ ID NO: 2838)3′-AAGAUUGUCCCUAUAAUAACUGAUUAU-5′ (SEQ ID NO: 4852) LDHA-1970 Target:5′-TTCTAACAGGGATATTATTGACTAATA-3′ (SEQ ID NO: 6866)5′-UAACAGGGAUAUUAUUGACUAAUag-3′ (SEQ ID NO: 2839)3′-AGAUUGUCCCUAUAAUAACUGAUUAUC-5′ (SEQ ID NO: 4853) LDHA-1971 Target:5′-TCTAACAGGGATATTATTGACTAATAG-3′ (SEQ ID NO: 6867)5′-AACAGGGAUAUUAUUGACUAAUAgc-3′ (SEQ ID NO: 2840)3′-GAUUGUCCCUAUAAUAACUGAUUAUCG-5′ (SEQ ID NO: 4854) LDHA-1972 Target:5′-CTAACAGGGATATTATTGACTAATAGC-3′ (SEQ ID NO: 6868)5′-ACAGGGAUAUUAUUGACUAAUAGca-3′ (SEQ ID NO: 2841)3′-AUUGUCCCUAUAAUAACUGAUUAUCGU-5′ (SEQ ID NO: 4855) LDHA-1973 Target:5′-TAACAGGGATATTATTGACTAATAGCA-3′ (SEQ ID NO: 6869)5′-CAGGGAUAUUAUUGACUAAUAGCag-3′ (SEQ ID NO: 2842)3′-UUGUCCCUAUAAUAACUGAUUAUCGUC-5′ (SEQ ID NO: 4856) LDHA-1974 Target:5′-AACAGGGATATTATTGACTAATAGCAG-3′ (SEQ ID NO: 6870)5′-AGGGAUAUUAUUGACUAAUAGCAga-3′ (SEQ ID NO: 2843)3′-UGUCCCUAUAAUAACUGAUUAUCGUCU-5′ (SEQ ID NO: 4857) LDHA-1975 Target:5′-ACAGGGATATTATTGACTAATAGCAGA-3′ (SEQ ID NO: 6871)5′-GGGAUAUUAUUGACUAAUAGCAGag-3′ (SEQ ID NO: 2844)3′-GUCCCUAUAAUAACUGAUUAUCGUCUC-5′ (SEQ ID NO: 4858) LDHA-1976 Target:5′-CAGGGATATTATTGACTAATAGCAGAG-3′ (SEQ ID NO: 6872)5′-GGAUAUUAUUGACUAAUAGCAGAgg-3′ (SEQ ID NO: 2845)3′-UCCCUAUAAUAACUGAUUAUCGUCUCC-5′ (SEQ ID NO: 4859) LDHA-1977 Target:5′-AGGGATATTATTGACTAATAGCAGAGG-3′ (SEQ ID NO: 6873)5′-GAUAUUAUUGACUAAUAGCAGAGga-3′ (SEQ ID NO: 2846)3′-CCCUAUAAUAACUGAUUAUCGUCUCCU-5′ (SEQ ID NO: 4860) LDHA-1978 Target:5′-GGGATATTATTGACTAATAGCAGAGGA-3′ (SEQ ID NO: 6874)5′-AUAUUAUUGACUAAUAGCAGAGGat-3′ (SEQ ID NO: 2847)3′-CCUAUAAUAACUGAUUAUCGUCUCCUA-5′ (SEQ ID NO: 4861) LDHA-1979 Target:5′-GGATATTATTGACTAATAGCAGAGGAT-3′ (SEQ ID NO: 6875)5′-UAUUAUUGACUAAUAGCAGAGGAtg-3′ (SEQ ID NO: 2848)3′-CUAUAAUAACUGAUUAUCGUCUCCUAC-5′ (SEQ ID NO: 4862) LDHA-1980 Target:5′-GATATTATTGACTAATAGCAGAGGATG-3′ (SEQ ID NO: 6876)5′-AUUAUUGACUAAUAGCAGAGGAUgt-3′ (SEQ ID NO: 2849)3′-UAUAAUAACUGAUUAUCGUCUCCUACA-5′ (SEQ ID NO: 4863) LDHA-1981 Target:5′-ATATTATTGACTAATAGCAGAGGATGT-3′ (SEQ ID NO: 6877)5′-UUAUUGACUAAUAGCAGAGGAUGta-3′ (SEQ ID NO: 2850)3′-AUAAUAACUGAUUAUCGUCUCCUACAU-5′ (SEQ ID NO: 4864) LDHA-1982 Target:5′-TATTATTGACTAATAGCAGAGGATGTA-3′ (SEQ ID NO: 6878)5′-UAUUGACUAAUAGCAGAGGAUGUaa-3′ (SEQ ID NO: 2851)3′-UAAUAACUGAUUAUCGUCUCCUACAUU-5′ (SEQ ID NO: 4865) LDHA-1983 Target:5′-ATTATTGACTAATAGCAGAGGATGTAA-3′ (SEQ ID NO: 6879)5′-AUUGACUAAUAGCAGAGGAUGUAat-3′ (SEQ ID NO: 2852)3′-AAUAACUGAUUAUCGUCUCCUACAUUA-5′ (SEQ ID NO: 4866) LDHA-1984 Target:5′-TTATTGACTAATAGCAGAGGATGTAAT-3′ (SEQ ID NO: 6880)5′-UUGACUAAUAGCAGAGGAUGUAAta-3′ (SEQ ID NO: 2853)3′-AUAACUGAUUAUCGUCUCCUACAUUAU-5′ (SEQ ID NO: 4867) LDHA-1985 Target:5′-TATTGACTAATAGCAGAGGATGTAATA-3′ (SEQ ID NO: 6881)5′-UGACUAAUAGCAGAGGAUGUAAUag-3′ (SEQ ID NO: 2854)3′-UAACUGAUUAUCGUCUCCUACAUUAUC-5′ (SEQ ID NO: 4868) LDHA-1986 Target:5′-ATTGACTAATAGCAGAGGATGTAATAG-3′ (SEQ ID NO: 6882)5′-GACUAAUAGCAGAGGAUGUAAUAgt-3′ (SEQ ID NO: 2855)3′-AACUGAUUAUCGUCUCCUACAUUAUCA-5′ (SEQ ID NO: 4869) LDHA-1987 Target:5′-TTGACTAATAGCAGAGGATGTAATAGT-3′ (SEQ ID NO: 6883)5′-ACUAAUAGCAGAGGAUGUAAUAGtc-3′ (SEQ ID NO: 2856)3′-ACUGAUUAUCGUCUCCUACAUUAUCAG-5′ (SEQ ID NO: 4870) LDHA-1988 Target:5′-TGACTAATAGCAGAGGATGTAATAGTC-3′ (SEQ ID NO: 6884)5′-CUAAUAGCAGAGGAUGUAAUAGUca-3′ (SEQ ID NO: 2857)3′-CUGAUUAUCGUCUCCUACAUUAUCAGU-5′ (SEQ ID NO: 4871) LDHA-1989 Target:5′-GACTAATAGCAGAGGATGTAATAGTCA-3′ (SEQ ID NO: 6885)5′-UAAUAGCAGAGGAUGUAAUAGUCaa-3′ (SEQ ID NO: 2858)3′-UGAUUAUCGUCUCCUACAUUAUCAGUU-5′ (SEQ ID NO: 4872) LDHA-1990 Target:5′-ACTAATAGCAGAGGATGTAATAGTCAA-3′ (SEQ ID NO: 6886)5′-AAUAGCAGAGGAUGUAAUAGUCAac-3′ (SEQ ID NO: 2859)3′-GAUUAUCGUCUCCUACAUUAUCAGUUG-5′ (SEQ ID NO: 4873) LDHA-1991 Target:5′-CTAATAGCAGAGGATGTAATAGTCAAC-3′ (SEQ ID NO: 6887)5′-AUAGCAGAGGAUGUAAUAGUCAAct-3′ (SEQ ID NO: 2860)3′-AUUAUCGUCUCCUACAUUAUCAGUUGA-5′ (SEQ ID NO: 4874) LDHA-1992 Target:5′-TAATAGCAGAGGATGTAATAGTCAACT-3′ (SEQ ID NO: 6888)5′-UAGCAGAGGAUGUAAUAGUCAACtg-3′ (SEQ ID NO: 2861)3′-UUAUCGUCUCCUACAUUAUCAGUUGAC-5′ (SEQ ID NO: 4875) LDHA-1993 Target:5′-AATAGCAGAGGATGTAATAGTCAACTG-3′ (SEQ ID NO: 6889)5′-AGCAGAGGAUGUAAUAGUCAACUga-3′ (SEQ ID NO: 2862)3′-UAUCGUCUCCUACAUUAUCAGUUGACU-5′ (SEQ ID NO: 4876) LDHA-1994 Target:5′-ATAGCAGAGGATGTAATAGTCAACTGA-3′ (SEQ ID NO: 6890)5′-GCAGAGGAUGUAAUAGUCAACUGag-3′ (SEQ ID NO: 2863)3′-AUCGUCUCCUACAUUAUCAGUUGACUC-5′ (SEQ ID NO: 4877) LDHA-1995 Target:5′-TAGCAGAGGATGTAATAGTCAACTGAG-3′ (SEQ ID NO: 6891)5′-CAGAGGAUGUAAUAGUCAACUGAgt-3′ (SEQ ID NO: 2864)3′-UCGUCUCCUACAUUAUCAGUUGACUCA-5′ (SEQ ID NO: 4878) LDHA-1996 Target:5′-AGCAGAGGATGTAATAGTCAACTGAGT-3′ (SEQ ID NO: 6892)5′-AGAGGAUGUAAUAGUCAACUGAGtt-3′ (SEQ ID NO: 2865)3′-CGUCUCCUACAUUAUCAGUUGACUCAA-5′ (SEQ ID NO: 4879) LDHA-1997 Target:5′-GCAGAGGATGTAATAGTCAACTGAGTT-3′ (SEQ ID NO: 6893)5′-GAGGAUGUAAUAGUCAACUGAGUtg-3′ (SEQ ID NO: 2866)3′-GUCUCCUACAUUAUCAGUUGACUCAAC-5′ (SEQ ID NO: 4880) LDHA-1998 Target:5′-CAGAGGATGTAATAGTCAACTGAGTTG-3′ (SEQ ID NO: 6894)5′-AGGAUGUAAUAGUCAACUGAGUUgt-3′ (SEQ ID NO: 2867)3′-UCUCCUACAUUAUCAGUUGACUCAACA-5′ (SEQ ID NO: 4881) LDHA-1999 Target:5′-AGAGGATGTAATAGTCAACTGAGTTGT-3′ (SEQ ID NO: 6895)5′-GGAUGUAAUAGUCAACUGAGUUGta-3′ (SEQ ID NO: 2868)3′-CUCCUACAUUAUCAGUUGACUCAACAU-5′ (SEQ ID NO: 4882) LDHA-2000 Target:5′-GAGGATGTAATAGTCAACTGAGTTGTA-3′ (SEQ ID NO: 6896)5′-GAUGUAAUAGUCAACUGAGUUGUat-3′ (SEQ ID NO: 2869)3′-UCCUACAUUAUCAGUUGACUCAACAUA-5′ (SEQ ID NO: 4883) LDHA-2001 Target:5′-AGGATGTAATAGTCAACTGAGTTGTAT-3′ (SEQ ID NO: 6897)5′-AUGUAAUAGUCAACUGAGUUGUAtt-3′ (SEQ ID NO: 2870)3′-CCUACAUUAUCAGUUGACUCAACAUAA-5′ (SEQ ID NO: 4884) LDHA-2002 Target:5′-GGATGTAATAGTCAACTGAGTTGTATT-3′ (SEQ ID NO: 6898)5′-UGUAAUAGUCAACUGAGUUGUAUtg-3′ (SEQ ID NO: 2871)3′-CUACAUUAUCAGUUGACUCAACAUAAC-5′ (SEQ ID NO: 4885) LDHA-2003 Target:5′-GATGTAATAGTCAACTGAGTTGTATTG-3′ (SEQ ID NO: 6899)5′-GUAAUAGUCAACUGAGUUGUAUUgg-3′ (SEQ ID NO: 2872)3′-UACAUUAUCAGUUGACUCAACAUAACC-5′ (SEQ ID NO: 4886) LDHA-2004 Target:5′-ATGTAATAGTCAACTGAGTTGTATTGG-3′ (SEQ ID NO: 6900)5′-UAAUAGUCAACUGAGUUGUAUUGgt-3′ (SEQ ID NO: 2873)3′-ACAUUAUCAGUUGACUCAACAUAACCA-5′ (SEQ ID NO: 4887) LDHA-2005 Target:5′-TGTAATAGTCAACTGAGTTGTATTGGT-3′ (SEQ ID NO: 6901)5′-AAUAGUCAACUGAGUUGUAUUGGta-3′ (SEQ ID NO: 2874)3′-CAUUAUCAGUUGACUCAACAUAACCAU-5′ (SEQ ID NO: 4888) LDHA-2006 Target:5′-GTAATAGTCAACTGAGTTGTATTGGTA-3′ (SEQ ID NO: 6902)5′-AUAGUCAACUGAGUUGUAUUGGUac-3′ (SEQ ID NO: 2875)3′-AUUAUCAGUUGACUCAACAUAACCAUG-5′ (SEQ ID NO: 4889) LDHA-2007 Target:5′-TAATAGTCAACTGAGTTGTATTGGTAC-3′ (SEQ ID NO: 6903)5′-UAGUCAACUGAGUUGUAUUGGUAcc-3′ (SEQ ID NO: 2876)3′-UUAUCAGUUGACUCAACAUAACCAUGG-5′ (SEQ ID NO: 4890) LDHA-2008 Target:5′-AATAGTCAACTGAGTTGTATTGGTACC-3′ (SEQ ID NO: 6904)5′-AGUCAACUGAGUUGUAUUGGUACca-3′ (SEQ ID NO: 2877)3′-UAUCAGUUGACUCAACAUAACCAUGGU-5′ (SEQ ID NO: 4891) LDHA-2009 Target:5′-ATAGTCAACTGAGTTGTATTGGTACCA-3′ (SEQ ID NO: 6905)5′-GUCAACUGAGUUGUAUUGGUACCac-3′ (SEQ ID NO: 2878)3′-AUCAGUUGACUCAACAUAACCAUGGUG-5′ (SEQ ID NO: 4892) LDHA-2010 Target:5′-TAGTCAACTGAGTTGTATTGGTACCAC-3′ (SEQ ID NO: 6906)5′-UCAACUGAGUUGUAUUGGUACCAct-3′ (SEQ ID NO: 2879)3′-UCAGUUGACUCAACAUAACCAUGGUGA-5′ (SEQ ID NO: 4893) LDHA-2011 Target:5′-AGTCAACTGAGTTGTATTGGTACCACT-3′ (SEQ ID NO: 6907)5′-CAACUGAGUUGUAUUGGUACCACtt-3′ (SEQ ID NO: 2880)3′-CAGUUGACUCAACAUAACCAUGGUGAA-5′ (SEQ ID NO: 4894) LDHA-2012 Target:5′-GTCAACTGAGTTGTATTGGTACCACTT-3′ (SEQ ID NO: 6908)5′-AACUGAGUUGUAUUGGUACCACUtc-3′ (SEQ ID NO: 2881)3′-AGUUGACUCAACAUAACCAUGGUGAAG-5′ (SEQ ID NO: 4895) LDHA-2013 Target:5′-TCAACTGAGTTGTATTGGTACCACTTC-3′ (SEQ ID NO: 6909)5′-ACUGAGUUGUAUUGGUACCACUUcc-3′ (SEQ ID NO: 2882)3′-GUUGACUCAACAUAACCAUGGUGAAGG-5′ (SEQ ID NO: 4896) LDHA-2014 Target:5′-CAACTGAGTTGTATTGGTACCACTTCC-3′ (SEQ ID NO: 6910)5′-CUGAGUUGUAUUGGUACCACUUCca-3′ (SEQ ID NO: 2883)3′-UUGACUCAACAUAACCAUGGUGAAGGU-5′ (SEQ ID NO: 4897) LDHA-2015 Target:5′-AACTGAGTTGTATTGGTACCACTTCCA-3′ (SEQ ID NO: 6911)5′-UGAGUUGUAUUGGUACCACUUCCat-3′ (SEQ ID NO: 2884)3′-UGACUCAACAUAACCAUGGUGAAGGUA-5′ (SEQ ID NO: 4898) LDHA-2016 Target:5′-ACTGAGTTGTATTGGTACCACTTCCAT-3′ (SEQ ID NO: 6912)5′-GAGUUGUAUUGGUACCACUUCCAtt-3′ (SEQ ID NO: 2885)3′-GACUCAACAUAACCAUGGUGAAGGUAA-5′ (SEQ ID NO: 4899) LDHA-2017 Target:5′-CTGAGTTGTATTGGTACCACTTCCATT-3′ (SEQ ID NO: 6913)5′-AGUUGUAUUGGUACCACUUCCAUtg-3′ (SEQ ID NO: 2886)3′-ACUCAACAUAACCAUGGUGAAGGUAAC-5′ (SEQ ID NO: 4900) LDHA-2018 Target:5′-TGAGTTGTATTGGTACCACTTCCATTG-3′ (SEQ ID NO: 6914)5′-GUUGUAUUGGUACCACUUCCAUUgt-3′ (SEQ ID NO: 2887)3′-CUCAACAUAACCAUGGUGAAGGUAACA-5′ (SEQ ID NO: 4901) LDHA-2019 Target:5′-GAGTTGTATTGGTACCACTTCCATTGT-3′ (SEQ ID NO: 6915)5′-UUGUAUUGGUACCACUUCCAUUGta-3′ (SEQ ID NO: 2888)3′-UCAACAUAACCAUGGUGAAGGUAACAU-5′ (SEQ ID NO: 4902) LDHA-2020 Target:5′-AGTTGTATTGGTACCACTTCCATTGTA-3′ (SEQ ID NO: 6916)5′-UGUAUUGGUACCACUUCCAUUGUaa-3′ (SEQ ID NO: 2889)3′-CAACAUAACCAUGGUGAAGGUAACAUU-5′ (SEQ ID NO: 4903) LDHA-2021 Target:5′-GTTGTATTGGTACCACTTCCATTGTAA-3′ (SEQ ID NO: 6917)5′-GUAUUGGUACCACUUCCAUUGUAag-3′ (SEQ ID NO: 2890)3′-AACAUAACCAUGGUGAAGGUAACAUUC-5′ (SEQ ID NO: 4904) LDHA-2022 Target:5′-TTGTATTGGTACCACTTCCATTGTAAG-3′ (SEQ ID NO: 6918)5′-UAUUGGUACCACUUCCAUUGUAAgt-3′ (SEQ ID NO: 2891)3′-ACAUAACCAUGGUGAAGGUAACAUUCA-5′ (SEQ ID NO: 4905) LDHA-2023 Target:5′-TGTATTGGTACCACTTCCATTGTAAGT-3′ (SEQ ID NO: 6919)5′-AUUGGUACCACUUCCAUUGUAAGtc-3′ (SEQ ID NO: 2892)3′-CAUAACCAUGGUGAAGGUAACAUUCAG-5′ (SEQ ID NO: 4906) LDHA-2024 Target:5′-GTATTGGTACCACTTCCATTGTAAGTC-3′ (SEQ ID NO: 6920)5′-UUGGUACCACUUCCAUUGUAAGUcc-3′ (SEQ ID NO: 2893)3′-AUAACCAUGGUGAAGGUAACAUUCAGG-5′ (SEQ ID NO: 4907) LDHA-2025 Target:5′-TATTGGTACCACTTCCATTGTAAGTCC-3′ (SEQ ID NO: 6921)5′-UGGUACCACUUCCAUUGUAAGUCcc-3′ (SEQ ID NO: 2894)3′-UAACCAUGGUGAAGGUAACAUUCAGGG-5′ (SEQ ID NO: 4908) LDHA-2026 Target:5′-ATTGGTACCACTTCCATTGTAAGTCCC-3′ (SEQ ID NO: 6922)5′-GGUACCACUUCCAUUGUAAGUCCca-3′ (SEQ ID NO: 2895)3′-AACCAUGGUGAAGGUAACAUUCAGGGU-5′ (SEQ ID NO: 4909) LDHA-2027 Target:5′-TTGGTACCACTTCCATTGTAAGTCCCA-3′ (SEQ ID NO: 6923)5′-GUACCACUUCCAUUGUAAGUCCCaa-3′ (SEQ ID NO: 2896)3′-ACCAUGGUGAAGGUAACAUUCAGGGUU-5′ (SEQ ID NO: 4910) LDHA-2028 Target:5′-TGGTACCACTTCCATTGTAAGTCCCAA-3′ (SEQ ID NO: 6924)5′-UACCACUUCCAUUGUAAGUCCCAaa-3′ (SEQ ID NO: 2897)3′-CCAUGGUGAAGGUAACAUUCAGGGUUU-5′ (SEQ ID NO: 4911) LDHA-2029 Target:5′-GGTACCACTTCCATTGTAAGTCCCAAA-3′ (SEQ ID NO: 6925)5′-ACCACUUCCAUUGUAAGUCCCAAag-3′ (SEQ ID NO: 2898)3′-CAUGGUGAAGGUAACAUUCAGGGUUUC-5′ (SEQ ID NO: 4912) LDHA-2030 Target:5′-GTACCACTTCCATTGTAAGTCCCAAAG-3′ (SEQ ID NO: 6926)5′-CCACUUCCAUUGUAAGUCCCAAAgt-3′ (SEQ ID NO: 2899)3′-AUGGUGAAGGUAACAUUCAGGGUUUCA-5′ (SEQ ID NO: 4913) LDHA-2031 Target:5′-TACCACTTCCATTGTAAGTCCCAAAGT-3′ (SEQ ID NO: 6927)5′-CACUUCCAUUGUAAGUCCCAAAGta-3′ (SEQ ID NO: 2900)3′-UGGUGAAGGUAACAUUCAGGGUUUCAU-5′ (SEQ ID NO: 4914) LDHA-2032 Target:5′-ACCACTTCCATTGTAAGTCCCAAAGTA-3′ (SEQ ID NO: 6928)5′-ACUUCCAUUGUAAGUCCCAAAGUat-3′ (SEQ ID NO: 2901)3′-GGUGAAGGUAACAUUCAGGGUUUCAUA-5′ (SEQ ID NO: 4915) LDHA-2033 Target:5′-CCACTTCCATTGTAAGTCCCAAAGTAT-3′ (SEQ ID NO: 6929)5′-CUUCCAUUGUAAGUCCCAAAGUAtt-3′ (SEQ ID NO: 2902)3′-GUGAAGGUAACAUUCAGGGUUUCAUAA-5′ (SEQ ID NO: 4916) LDHA-2034 Target:5′-CACTTCCATTGTAAGTCCCAAAGTATT-3′ (SEQ ID NO: 6930)5′-UUCCAUUGUAAGUCCCAAAGUAUta-3′ (SEQ ID NO: 2903)3′-UGAAGGUAACAUUCAGGGUUUCAUAAU-5′ (SEQ ID NO: 4917) LDHA-2035 Target:5′-ACTTCCATTGTAAGTCCCAAAGTATTA-3′ (SEQ ID NO: 6931)5′-UCCAUUGUAAGUCCCAAAGUAUUat-3′ (SEQ ID NO: 2904)3′-GAAGGUAACAUUCAGGGUUUCAUAAUA-5′ (SEQ ID NO: 4918) LDHA-2036 Target:5′-CTTCCATTGTAAGTCCCAAAGTATTAT-3′ (SEQ ID NO: 6932)5′-CCAUUGUAAGUCCCAAAGUAUUAta-3′ (SEQ ID NO: 2905)3′-AAGGUAACAUUCAGGGUUUCAUAAUAU-5′ (SEQ ID NO: 4919) LDHA-2037 Target:5′-TTCCATTGTAAGTCCCAAAGTATTATA-3′ (SEQ ID NO: 6933)5′-CAUUGUAAGUCCCAAAGUAUUAUat-3′ (SEQ ID NO: 2906)3′-AGGUAACAUUCAGGGUUUCAUAAUAUA-5′ (SEQ ID NO: 4920) LDHA-2038 Target:5′-TCCATTGTAAGTCCCAAAGTATTATAT-3′ (SEQ ID NO: 6934)5′-AUUGUAAGUCCCAAAGUAUUAUAta-3′ (SEQ ID NO: 2907)3′-GGUAACAUUCAGGGUUUCAUAAUAUAU-5′ (SEQ ID NO: 4921) LDHA-2039 Target:5′-CCATTGTAAGTCCCAAAGTATTATATA-3′ (SEQ ID NO: 6935)5′-UUGUAAGUCCCAAAGUAUUAUAUat-3′ (SEQ ID NO: 2908)3′-GUAACAUUCAGGGUUUCAUAAUAUAUA-5′ (SEQ ID NO: 4922) LDHA-2040 Target:5′-CATTGTAAGTCCCAAAGTATTATATAT-3′ (SEQ ID NO: 6936)5′-UGUAAGUCCCAAAGUAUUAUAUAtt-3′ (SEQ ID NO: 2909)3′-UAACAUUCAGGGUUUCAUAAUAUAUAA-5′ (SEQ ID NO: 4923) LDHA-2041 Target:5′-ATTGTAAGTCCCAAAGTATTATATATT-3′ (SEQ ID NO: 6937)5′-GUAAGUCCCAAAGUAUUAUAUAUtt-3′ (SEQ ID NO: 2910)3′-AACAUUCAGGGUUUCAUAAUAUAUAAA-5′ (SEQ ID NO: 4924) LDHA-2042 Target:5′-TTGTAAGTCCCAAAGTATTATATATTT-3′ (SEQ ID NO: 6938)5′-UAAGUCCCAAAGUAUUAUAUAUUtg-3′ (SEQ ID NO: 2911)3′-ACAUUCAGGGUUUCAUAAUAUAUAAAC-5′ (SEQ ID NO: 4925) LDHA-2043 Target:5′-TGTAAGTCCCAAAGTATTATATATTTG-3′ (SEQ ID NO: 6939)5′-AAGUCCCAAAGUAUUAUAUAUUUga-3′ (SEQ ID NO: 2912)3′-CAUUCAGGGUUUCAUAAUAUAUAAACU-5′ (SEQ ID NO: 4926) LDHA-2044 Target:5′-GTAAGTCCCAAAGTATTATATATTTGA-3′ (SEQ ID NO: 6940)5′-AGUCCCAAAGUAUUAUAUAUUUGat-3′ (SEQ ID NO: 2913)3′-AUUCAGGGUUUCAUAAUAUAUAAACUA-5′ (SEQ ID NO: 4927) LDHA-2045 Target:5′-TAAGTCCCAAAGTATTATATATTTGAT-3′ (SEQ ID NO: 6941)5′-GUCCCAAAGUAUUAUAUAUUUGAta-3′ (SEQ ID NO: 2914)3′-UUCAGGGUUUCAUAAUAUAUAAACUAU-5′ (SEQ ID NO: 4928) LDHA-2046 Target:5′-AAGTCCCAAAGTATTATATATTTGATA-3′ (SEQ ID NO: 6942)5′-UCCCAAAGUAUUAUAUAUUUGAUaa-3′ (SEQ ID NO: 2915)3′-UCAGGGUUUCAUAAUAUAUAAACUAUU-5′ (SEQ ID NO: 4929) LDHA-2047 Target:5′-AGTCCCAAAGTATTATATATTTGATAA-3′ (SEQ ID NO: 6943)5′-CCCAAAGUAUUAUAUAUUUGAUAat-3′ (SEQ ID NO: 2916)3′-CAGGGUUUCAUAAUAUAUAAACUAUUA-5′ (SEQ ID NO: 4930) LDHA-2048 Target:5′-GTCCCAAAGTATTATATATTTGATAAT-3′ (SEQ ID NO: 6944)5′-CCAAAGUAUUAUAUAUUUGAUAAta-3′ (SEQ ID NO: 2917)3′-AGGGUUUCAUAAUAUAUAAACUAUUAU-5′ (SEQ ID NO: 4931) LDHA-2049 Target:5′-TCCCAAAGTATTATATATTTGATAATA-3′ (SEQ ID NO: 6945)5′-CAAAGUAUUAUAUAUUUGAUAAUaa-3′ (SEQ ID NO: 2918)3′-GGGUUUCAUAAUAUAUAAACUAUUAUU-5′ (SEQ ID NO: 4932) LDHA-2050 Target:5′-CCCAAAGTATTATATATTTGATAATAA-3′ (SEQ ID NO: 6946)5′-AAAGUAUUAUAUAUUUGAUAAUAat-3′ (SEQ ID NO: 2919)3′-GGUUUCAUAAUAUAUAAACUAUUAUUA-5′ (SEQ ID NO: 4933) LDHA-2051 Target:5′-CCAAAGTATTATATATTTGATAATAAT-3′ (SEQ ID NO: 6947)5′-AAGUAUUAUAUAUUUGAUAAUAAtg-3′ (SEQ ID NO: 2920)3′-GUUUCAUAAUAUAUAAACUAUUAUUAC-5′ (SEQ ID NO: 4934) LDHA-2052 Target:5′-CAAAGTATTATATATTTGATAATAATG-3′ (SEQ ID NO: 6948)5′-AGUAUUAUAUAUUUGAUAAUAAUgc-3′ (SEQ ID NO: 2921)3′-UUUCAUAAUAUAUAAACUAUUAUUACG-5′ (SEQ ID NO: 4935) LDHA-2053 Target:5′-AAAGTATTATATATTTGATAATAATGC-3′ (SEQ ID NO: 6949)5′-GUAUUAUAUAUUUGAUAAUAAUGct-3′ (SEQ ID NO: 2922)3′-UUCAUAAUAUAUAAACUAUUAUUACGA-5′ (SEQ ID NO: 4936) LDHA-2054 Target:5′-AAGTATTATATATTTGATAATAATGCT-3′ (SEQ ID NO: 6950)5′-UAUUAUAUAUUUGAUAAUAAUGCta-3′ (SEQ ID NO: 2923)3′-UCAUAAUAUAUAAACUAUUAUUACGAU-5′ (SEQ ID NO: 4937) LDHA-2055 Target:5′-AGTATTATATATTTGATAATAATGCTA-3′ (SEQ ID NO: 6951)5′-AUUAUAUAUUUGAUAAUAAUGCUaa-3′ (SEQ ID NO: 2924)3′-CAUAAUAUAUAAACUAUUAUUACGAUU-5′ (SEQ ID NO: 4938) LDHA-2056 Target:5′-GTATTATATATTTGATAATAATGCTAA-3′ (SEQ ID NO: 6952)5′-UUAUAUAUUUGAUAAUAAUGCUAat-3′ (SEQ ID NO: 2925)3′-AUAAUAUAUAAACUAUUAUUACGAUUA-5′ (SEQ ID NO: 4939) LDHA-2057 Target:5′-TATTATATATTTGATAATAATGCTAAT-3′ (SEQ ID NO: 6953)5′-UAUAUAUUUGAUAAUAAUGCUAAtc-3′ (SEQ ID NO: 2926)3′-UAAUAUAUAAACUAUUAUUACGAUUAG-5′ (SEQ ID NO: 4940) LDHA-2058 Target:5′-ATTATATATTTGATAATAATGCTAATC-3′ (SEQ ID NO: 6954)5′-AUAUAUUUGAUAAUAAUGCUAAUca-3′ (SEQ ID NO: 2927)3′-AAUAUAUAAACUAUUAUUACGAUUAGU-5′ (SEQ ID NO: 4941) LDHA-2059 Target:5′-TTATATATTTGATAATAATGCTAATCA-3′ (SEQ ID NO: 6955)5′-UAUAUUUGAUAAUAAUGCUAAUCat-3′ (SEQ ID NO: 2928)3′-AUAUAUAAACUAUUAUUACGAUUAGUA-5′ (SEQ ID NO: 4942) LDHA-2060 Target:5′-TATATATTTGATAATAATGCTAATCAT-3′ (SEQ ID NO: 6956)5′-AUAUUUGAUAAUAAUGCUAAUCAta-3′ (SEQ ID NO: 2929)3′-UAUAUAAACUAUUAUUACGAUUAGUAU-5′ (SEQ ID NO: 4943) LDHA-2061 Target:5′-ATATATTTGATAATAATGCTAATCATA-3′ (SEQ ID NO: 6957)5′-UAUUUGAUAAUAAUGCUAAUCAUaa-3′ (SEQ ID NO: 2930)3′-AUAUAAACUAUUAUUACGAUUAGUAUU-5′ (SEQ ID NO: 4944) LDHA-2062 Target:5′-TATATTTGATAATAATGCTAATCATAA-3′ (SEQ ID NO: 6958)5′-AUUUGAUAAUAAUGCUAAUCAUAat-3′ (SEQ ID NO: 2931)3′-UAUAAACUAUUAUUACGAUUAGUAUUA-5′ (SEQ ID NO: 4945) LDHA-2063 Target:5′-ATATTTGATAATAATGCTAATCATAAT-3′ (SEQ ID NO: 6959)5′-UUUGAUAAUAAUGCUAAUCAUAAtt-3′ (SEQ ID NO: 2932)3′-AUAAACUAUUAUUACGAUUAGUAUUAA-5′ (SEQ ID NO: 4946) LDHA-2064 Target:5′-TATTTGATAATAATGCTAATCATAATT-3′ (SEQ ID NO: 6960)5′-UUGAUAAUAAUGCUAAUCAUAAUtg-3′ (SEQ ID NO: 2933)3′-UAAACUAUUAUUACGAUUAGUAUUAAC-5′ (SEQ ID NO: 4947) LDHA-2065 Target:5′-ATTTGATAATAATGCTAATCATAATTG-3′ (SEQ ID NO: 6961)5′-UGAUAAUAAUGCUAAUCAUAAUUgg-3′ (SEQ ID NO: 2934)3′-AAACUAUUAUUACGAUUAGUAUUAACC-5′ (SEQ ID NO: 4948) LDHA-2066 Target:5′-TTTGATAATAATGCTAATCATAATTGG-3′ (SEQ ID NO: 6962)5′-GAUAAUAAUGCUAAUCAUAAUUGga-3′ (SEQ ID NO: 2935)3′-AACUAUUAUUACGAUUAGUAUUAACCU-5′ (SEQ ID NO: 4949) LDHA-2067 Target:5′-TTGATAATAATGCTAATCATAATTGGA-3′ (SEQ ID NO: 6963)5′-AUAAUAAUGCUAAUCAUAAUUGGaa-3′ (SEQ ID NO: 2936)3′-ACUAUUAUUACGAUUAGUAUUAACCUU-5′ (SEQ ID NO: 4950) LDHA-2068 Target:5′-TGATAATAATGCTAATCATAATTGGAA-3′ (SEQ ID NO: 6964)5′-UAAUAAUGCUAAUCAUAAUUGGAaa-3′ (SEQ ID NO: 2937)3′-CUAUUAUUACGAUUAGUAUUAACCUUU-5′ (SEQ ID NO: 4951) LDHA-2069 Target:5′-GATAATAATGCTAATCATAATTGGAAA-3′ (SEQ ID NO: 6965)5′-AAUAAUGCUAAUCAUAAUUGGAAag-3′ (SEQ ID NO: 2938)3′-UAUUAUUACGAUUAGUAUUAACCUUUC-5′ (SEQ ID NO: 4952) LDHA-2070 Target:5′-ATAATAATGCTAATCATAATTGGAAAG-3′ (SEQ ID NO: 6966)5′-AUAAUGCUAAUCAUAAUUGGAAAgt-3′ (SEQ ID NO: 2939)3′-AUUAUUACGAUUAGUAUUAACCUUUCA-5′ (SEQ ID NO: 4953) LDHA-2071 Target:5′-TAATAATGCTAATCATAATTGGAAAGT-3′ (SEQ ID NO: 6967)5′-UAAUGCUAAUCAUAAUUGGAAAGta-3′ (SEQ ID NO: 2940)3′-UUAUUACGAUUAGUAUUAACCUUUCAU-5′ (SEQ ID NO: 4954) LDHA-2072 Target:5′-AATAATGCTAATCATAATTGGAAAGTA-3′ (SEQ ID NO: 6968)5′-AAUGCUAAUCAUAAUUGGAAAGUaa-3′ (SEQ ID NO: 2941)3′-UAUUACGAUUAGUAUUAACCUUUCAUU-5′ (SEQ ID NO: 4955) LDHA-2073 Target:5′-ATAATGCTAATCATAATTGGAAAGTAA-3′ (SEQ ID NO: 6969)5′-AUGCUAAUCAUAAUUGGAAAGUAac-3′ (SEQ ID NO: 2942)3′-AUUACGAUUAGUAUUAACCUUUCAUUG-5′ (SEQ ID NO: 4956) LDHA-2074 Target:5′-TAATGCTAATCATAATTGGAAAGTAAC-3′ (SEQ ID NO: 6970)5′-UGCUAAUCAUAAUUGGAAAGUAAca-3′ (SEQ ID NO: 2943)3′-UUACGAUUAGUAUUAACCUUUCAUUGU-5′ (SEQ ID NO: 4957) LDHA-2075 Target:5′-AATGCTAATCATAATTGGAAAGTAACA-3′ (SEQ ID NO: 6971)5′-GCUAAUCAUAAUUGGAAAGUAACat-3′ (SEQ ID NO: 2944)3′-UACGAUUAGUAUUAACCUUUCAUUGUA-5′ (SEQ ID NO: 4958) LDHA-2076 Target:5′-ATGCTAATCATAATTGGAAAGTAACAT-3′ (SEQ ID NO: 6972)5′-CUAAUCAUAAUUGGAAAGUAACAtt-3′ (SEQ ID NO: 2945)3′-ACGAUUAGUAUUAACCUUUCAUUGUAA-5′ (SEQ ID NO: 4959) LDHA-2077 Target:5′-TGCTAATCATAATTGGAAAGTAACATT-3′ (SEQ ID NO: 6973)5′-UAAUCAUAAUUGGAAAGUAACAUtc-3′ (SEQ ID NO: 2946)3′-CGAUUAGUAUUAACCUUUCAUUGUAAG-5′ (SEQ ID NO: 4960) LDHA-2078 Target:5′-GCTAATCATAATTGGAAAGTAACATTC-3′ (SEQ ID NO: 6974)5′-AAUCAUAAUUGGAAAGUAACAUUct-3′ (SEQ ID NO: 2947)3′-GAUUAGUAUUAACCUUUCAUUGUAAGA-5′ (SEQ ID NO: 4961) LDHA-2079 Target:5′-CTAATCATAATTGGAAAGTAACATTCT-3′ (SEQ ID NO: 6975)5′-AUCAUAAUUGGAAAGUAACAUUCta-3′ (SEQ ID NO: 2948)3′-AUUAGUAUUAACCUUUCAUUGUAAGAU-5′ (SEQ ID NO: 4962) LDHA-2080 Target:5′-TAATCATAATTGGAAAGTAACATTCTA-3′ (SEQ ID NO: 6976)5′-UCAUAAUUGGAAAGUAACAUUCUat-3′ (SEQ ID NO: 2949)3′-UUAGUAUUAACCUUUCAUUGUAAGAUA-5′ (SEQ ID NO: 4963) LDHA-2081 Target:5′-AATCATAATTGGAAAGTAACATTCTAT-3′ (SEQ ID NO: 6977)5′-CAUAAUUGGAAAGUAACAUUCUAta-3′ (SEQ ID NO: 2950)3′-UAGUAUUAACCUUUCAUUGUAAGAUAU-5′ (SEQ ID NO: 4964) LDHA-2082 Target:5′-ATCATAATTGGAAAGTAACATTCTATA-3′ (SEQ ID NO: 6978)5′-AUAAUUGGAAAGUAACAUUCUAUat-3′ (SEQ ID NO: 2951)3′-AGUAUUAACCUUUCAUUGUAAGAUAUA-5′ (SEQ ID NO: 4965) LDHA-2083 Target:5′-TCATAATTGGAAAGTAACATTCTATAT-3′ (SEQ ID NO: 6979)5′-UAAUUGGAAAGUAACAUUCUAUAtg-3′ (SEQ ID NO: 2952)3′-GUAUUAACCUUUCAUUGUAAGAUAUAC-5′ (SEQ ID NO: 4966) LDHA-2084 Target:5′-CATAATTGGAAAGTAACATTCTATATG-3′ (SEQ ID NO: 6980)5′-AAUUGGAAAGUAACAUUCUAUAUgt-3′ (SEQ ID NO: 2953)3′-UAUUAACCUUUCAUUGUAAGAUAUACA-5′ (SEQ ID NO: 4967) LDHA-2085 Target:5′-ATAATTGGAAAGTAACATTCTATATGT-3′ (SEQ ID NO: 6981)5′-AUUGGAAAGUAACAUUCUAUAUGta-3′ (SEQ ID NO: 2954)3′-AUUAACCUUUCAUUGUAAGAUAUACAU-5′ (SEQ ID NO: 4968) LDHA-2086 Target:5′-TAATTGGAAAGTAACATTCTATATGTA-3′ (SEQ ID NO: 6982)5′-UUGGAAAGUAACAUUCUAUAUGUaa-3′ (SEQ ID NO: 2955)3′-UUAACCUUUCAUUGUAAGAUAUACAUU-5′ (SEQ ID NO: 4969) LDHA-2087 Target:5′-AATTGGAAAGTAACATTCTATATGTAA-3′ (SEQ ID NO: 6983)5′-UGGAAAGUAACAUUCUAUAUGUAaa-3′ (SEQ ID NO: 2956)3′-UAACCUUUCAUUGUAAGAUAUACAUUU-5′ (SEQ ID NO: 4970) LDHA-2088 Target:5′-ATTGGAAAGTAACATTCTATATGTAAA-3′ (SEQ ID NO: 6984)5′-GGAAAGUAACAUUCUAUAUGUAAat-3′ (SEQ ID NO: 2957)3′-AACCUUUCAUUGUAAGAUAUACAUUUA-5′ (SEQ ID NO: 4971) LDHA-2089 Target:5′-TTGGAAAGTAACATTCTATATGTAAAT-3′ (SEQ ID NO: 6985)5′-GAAAGUAACAUUCUAUAUGUAAAtg-3′ (SEQ ID NO: 2958)3′-ACCUUUCAUUGUAAGAUAUACAUUUAC-5′ (SEQ ID NO: 4972) LDHA-2090 Target:5′-TGGAAAGTAACATTCTATATGTAAATG-3′ (SEQ ID NO: 6986)5′-AAAGUAACAUUCUAUAUGUAAAUgt-3′ (SEQ ID NO: 2959)3′-CCUUUCAUUGUAAGAUAUACAUUUACA-5′ (SEQ ID NO: 4973) LDHA-2091 Target:5′-GGAAAGTAACATTCTATATGTAAATGT-3′ (SEQ ID NO: 6987)5′-AAGUAACAUUCUAUAUGUAAAUGta-3′ (SEQ ID NO: 2960)3′-CUUUCAUUGUAAGAUAUACAUUUACAU-5′ (SEQ ID NO: 4974) LDHA-2092 Target:5′-GAAAGTAACATTCTATATGTAAATGTA-3′ (SEQ ID NO: 6988)5′-AGUAACAUUCUAUAUGUAAAUGUaa-3′ (SEQ ID NO: 2961)3′-UUUCAUUGUAAGAUAUACAUUUACAUU-5′ (SEQ ID NO: 4975) LDHA-2093 Target:5′-AAAGTAACATTCTATATGTAAATGTAA-3′ (SEQ ID NO: 6989)5′-GUAACAUUCUAUAUGUAAAUGUAaa-3′ (SEQ ID NO: 2962)3′-UUCAUUGUAAGAUAUACAUUUACAUUU-5′ (SEQ ID NO: 4976) LDHA-2094 Target:5′-AAGTAACATTCTATATGTAAATGTAAA-3′ (SEQ ID NO: 6990)5′-UAACAUUCUAUAUGUAAAUGUAAaa-3′ (SEQ ID NO: 2963)3′-UCAUUGUAAGAUAUACAUUUACAUUUU-5′ (SEQ ID NO: 4977) LDHA-2095 Target:5′-AGTAACATTCTATATGTAAATGTAAAA-3′ (SEQ ID NO: 6991)5′-AACAUUCUAUAUGUAAAUGUAAAat-3′ (SEQ ID NO: 2964)3′-CAUUGUAAGAUAUACAUUUACAUUUUA-5′ (SEQ ID NO: 4978) LDHA-2096 Target:5′-GTAACATTCTATATGTAAATGTAAAAT-3′ (SEQ ID NO: 6992)5′-ACAUUCUAUAUGUAAAUGUAAAAtt-3′ (SEQ ID NO: 2965)3′-AUUGUAAGAUAUACAUUUACAUUUUAA-5′ (SEQ ID NO: 4979) LDHA-2097 Target:5′-TAACATTCTATATGTAAATGTAAAATT-3′ (SEQ ID NO: 6993)5′-CAUUCUAUAUGUAAAUGUAAAAUtt-3′ (SEQ ID NO: 2966)3′-UUGUAAGAUAUACAUUUACAUUUUAAA-5′ (SEQ ID NO: 4980) LDHA-2098 Target:5′-AACATTCTATATGTAAATGTAAAATTT-3′ (SEQ ID NO: 6994)5′-AUUCUAUAUGUAAAUGUAAAAUUta-3′ (SEQ ID NO: 2967)3′-UGUAAGAUAUACAUUUACAUUUUAAAU-5′ (SEQ ID NO: 4981) LDHA-2099 Target:5′-ACATTCTATATGTAAATGTAAAATTTA-3′ (SEQ ID NO: 6995)5′-UUCUAUAUGUAAAUGUAAAAUUUat-3′ (SEQ ID NO: 2968)3′-GUAAGAUAUACAUUUACAUUUUAAAUA-5′ (SEQ ID NO: 4982) LDHA-2100 Target:5′-CATTCTATATGTAAATGTAAAATTTAT-3′ (SEQ ID NO: 6996)5′-UCUAUAUGUAAAUGUAAAAUUUAtt-3′ (SEQ ID NO: 2969)3′-UAAGAUAUACAUUUACAUUUUAAAUAA-5′ (SEQ ID NO: 4983) LDHA-2101 Target:5′-ATTCTATATGTAAATGTAAAATTTATT-3′ (SEQ ID NO: 6997)5′-CUAUAUGUAAAUGUAAAAUUUAUtt-3′ (SEQ ID NO: 2970)3′-AAGAUAUACAUUUACAUUUUAAAUAAA-5′ (SEQ ID NO: 4984) LDHA-2102 Target:5′-TTCTATATGTAAATGTAAAATTTATTT-3′ (SEQ ID NO: 6998)5′-UAUAUGUAAAUGUAAAAUUUAUUtg-3′ (SEQ ID NO: 2971)3′-AGAUAUACAUUUACAUUUUAAAUAAAC-5′ (SEQ ID NO: 4985) LDHA-2103 Target:5′-TCTATATGTAAATGTAAAATTTATTTG-3′ (SEQ ID NO: 6999)5′-AUAUGUAAAUGUAAAAUUUAUUUgc-3′ (SEQ ID NO: 2972)3′-GAUAUACAUUUACAUUUUAAAUAAACG-5′ (SEQ ID NO: 4986) LDHA-2104 Target:5′-CTATATGTAAATGTAAAATTTATTTGC-3′ (SEQ ID NO: 7000)5′-UAUGUAAAUGUAAAAUUUAUUUGcc-3′ (SEQ ID NO: 2973)3′-AUAUACAUUUACAUUUUAAAUAAACGG-5′ (SEQ ID NO: 4987) LDHA-2105 Target:5′-TATATGTAAATGTAAAATTTATTTGCC-3′ (SEQ ID NO: 7001)5′-AUGUAAAUGUAAAAUUUAUUUGCca-3′ (SEQ ID NO: 2974)3′-UAUACAUUUACAUUUUAAAUAAACGGU-5′ (SEQ ID NO: 4988) LDHA-2106 Target:5′-ATATGTAAATGTAAAATTTATTTGCCA-3′ (SEQ ID NO: 7002)5′-UGUAAAUGUAAAAUUUAUUUGCCaa-3′ (SEQ ID NO: 2975)3′-AUACAUUUACAUUUUAAAUAAACGGUU-5′ (SEQ ID NO: 4989) LDHA-2107 Target:5′-TATGTAAATGTAAAATTTATTTGCCAA-3′ (SEQ ID NO: 7003)5′-GUAAAUGUAAAAUUUAUUUGCCAac-3′ (SEQ ID NO: 2976)3′-UACAUUUACAUUUUAAAUAAACGGUUG-5′ (SEQ ID NO: 4990) LDHA-2108 Target:5′-ATGTAAATGTAAAATTTATTTGCCAAC-3′ (SEQ ID NO: 7004)5′-UAAAUGUAAAAUUUAUUUGCCAAct-3′ (SEQ ID NO: 2977)3′-ACAUUUACAUUUUAAAUAAACGGUUGA-5′ (SEQ ID NO: 4991) LDHA-2109 Target:5′-TGTAAATGTAAAATTTATTTGCCAACT-3′ (SEQ ID NO: 7005)5′-AAAUGUAAAAUUUAUUUGCCAACtg-3′ (SEQ ID NO: 2978)3′-CAUUUACAUUUUAAAUAAACGGUUGAC-5′ (SEQ ID NO: 4992) LDHA-2110 Target:5′-GTAAATGTAAAATTTATTTGCCAACTG-3′ (SEQ ID NO: 7006)5′-AAUGUAAAAUUUAUUUGCCAACUga-3′ (SEQ ID NO: 2979)3′-AUUUACAUUUUAAAUAAACGGUUGACU-5′ (SEQ ID NO: 4993) LDHA-2111 Target:5′-TAAATGTAAAATTTATTTGCCAACTGA-3′ (SEQ ID NO: 7007)5′-AUGUAAAAUUUAUUUGCCAACUGaa-3′ (SEQ ID NO: 2980)3′-UUUACAUUUUAAAUAAACGGUUGACUU-5′ (SEQ ID NO: 4994) LDHA-2112 Target:5′-AAATGTAAAATTTATTTGCCAACTGAA-3′ (SEQ ID NO: 7008)5′-UGUAAAAUUUAUUUGCCAACUGAat-3′ (SEQ ID NO: 2981)3′-UUACAUUUUAAAUAAACGGUUGACUUA-5′ (SEQ ID NO: 4995) LDHA-2113 Target:5′-AATGTAAAATTTATTTGCCAACTGAAT-3′ (SEQ ID NO: 7009)5′-GUAAAAUUUAUUUGCCAACUGAAta-3′ (SEQ ID NO: 2982)3′-UACAUUUUAAAUAAACGGUUGACUUAU-5′ (SEQ ID NO: 4996) LDHA-2114 Target:5′-ATGTAAAATTTATTTGCCAACTGAATA-3′ (SEQ ID NO: 7010)5′-UAAAAUUUAUUUGCCAACUGAAUat-3′ (SEQ ID NO: 2983)3′-ACAUUUUAAAUAAACGGUUGACUUAUA-5′ (SEQ ID NO: 4997) LDHA-2115 Target:5′-TGTAAAATTTATTTGCCAACTGAATAT-3′ (SEQ ID NO: 7011)5′-AAAAUUUAUUUGCCAACUGAAUAta-3′ (SEQ ID NO: 2984)3′-CAUUUUAAAUAAACGGUUGACUUAUAU-5′ (SEQ ID NO: 4998) LDHA-2116 Target:5′-GTAAAATTTATTTGCCAACTGAATATA-3′ (SEQ ID NO: 7012)5′-AAAUUUAUUUGCCAACUGAAUAUag-3′ (SEQ ID NO: 2985)3′-AUUUUAAAUAAACGGUUGACUUAUAUC-5′ (SEQ ID NO: 4999) LDHA-2117 Target:5′-TAAAATTTATTTGCCAACTGAATATAG-3′ (SEQ ID NO: 7013)5′-AAUUUAUUUGCCAACUGAAUAUAgg-3′ (SEQ ID NO: 2986)3′-UUUUAAAUAAACGGUUGACUUAUAUCC-5′ (SEQ ID NO: 5000) LDHA-2118 Target:5′-AAAATTTATTTGCCAACTGAATATAGG-3′ (SEQ ID NO: 7014)5′-AUUUAUUUGCCAACUGAAUAUAGgc-3′ (SEQ ID NO: 2987)3′-UUUAAAUAAACGGUUGACUUAUAUCCG-5′ (SEQ ID NO: 5001) LDHA-2119 Target:5′-AAATTTATTTGCCAACTGAATATAGGC-3′ (SEQ ID NO: 7015)5′-UUUAUUUGCCAACUGAAUAUAGGca-3′ (SEQ ID NO: 2988)3′-UUAAAUAAACGGUUGACUUAUAUCCGU-5′ (SEQ ID NO: 5002) LDHA-2120 Target:5′-AATTTATTTGCCAACTGAATATAGGCA-3′ (SEQ ID NO: 7016)5′-UUAUUUGCCAACUGAAUAUAGGCaa-3′ (SEQ ID NO: 2989)3′-UAAAUAAACGGUUGACUUAUAUCCGUU-5′ (SEQ ID NO: 5003) LDHA-2121 Target:5′-ATTTATTTGCCAACTGAATATAGGCAA-3′ (SEQ ID NO: 7017)5′-UAUUUGCCAACUGAAUAUAGGCAat-3′ (SEQ ID NO: 2990)3′-AAAUAAACGGUUGACUUAUAUCCGUUA-5′ (SEQ ID NO: 5004) LDHA-2122 Target:5′-TTTATTTGCCAACTGAATATAGGCAAT-3′ (SEQ ID NO: 7018)5′-AUUUGCCAACUGAAUAUAGGCAAtg-3′ (SEQ ID NO: 2991)3′-AAUAAACGGUUGACUUAUAUCCGUUAC-5′ (SEQ ID NO: 5005) LDHA-2123 Target:5′-TTATTTGCCAACTGAATATAGGCAATG-3′ (SEQ ID NO: 7019)5′-UUUGCCAACUGAAUAUAGGCAAUga-3′ (SEQ ID NO: 2992)3′-AUAAACGGUUGACUUAUAUCCGUUACU-5′ (SEQ ID NO: 5006) LDHA-2124 Target:5′-TATTTGCCAACTGAATATAGGCAATGA-3′ (SEQ ID NO: 7020)5′-UUGCCAACUGAAUAUAGGCAAUGat-3′ (SEQ ID NO: 2993)3′-UAAACGGUUGACUUAUAUCCGUUACUA-5′ (SEQ ID NO: 5007) LDHA-2125 Target:5′-ATTTGCCAACTGAATATAGGCAATGAT-3′ (SEQ ID NO: 7021)5′-UGCCAACUGAAUAUAGGCAAUGAta-3′ (SEQ ID NO: 2994)3′-AAACGGUUGACUUAUAUCCGUUACUAU-5′ (SEQ ID NO: 5008) LDHA-2126 Target:5′-TTTGCCAACTGAATATAGGCAATGATA-3′ (SEQ ID NO: 7022)5′-GCCAACUGAAUAUAGGCAAUGAUag-3′ (SEQ ID NO: 2995)3′-AACGGUUGACUUAUAUCCGUUACUAUC-5′ (SEQ ID NO: 5009) LDHA-2127 Target:5′-TTGCCAACTGAATATAGGCAATGATAG-3′ (SEQ ID NO: 7023)5′-CCAACUGAAUAUAGGCAAUGAUAgt-3′ (SEQ ID NO: 2996)3′-ACGGUUGACUUAUAUCCGUUACUAUCA-5′ (SEQ ID NO: 5010) LDHA-2128 Target:5′-TGCCAACTGAATATAGGCAATGATAGT-3′ (SEQ ID NO: 7024)5′-CAACUGAAUAUAGGCAAUGAUAGtg-3′ (SEQ ID NO: 2997)3′-CGGUUGACUUAUAUCCGUUACUAUCAC-5′ (SEQ ID NO: 5011) LDHA-2129 Target:5′-GCCAACTGAATATAGGCAATGATAGTG-3′ (SEQ ID NO: 7025)5′-AACUGAAUAUAGGCAAUGAUAGUgt-3′ (SEQ ID NO: 2998)3′-GGUUGACUUAUAUCCGUUACUAUCACA-5′ (SEQ ID NO: 5012) LDHA-2130 Target:5′-CCAACTGAATATAGGCAATGATAGTGT-3′ (SEQ ID NO: 7026)5′-ACUGAAUAUAGGCAAUGAUAGUGtg-3′ (SEQ ID NO: 2999)3′-GUUGACUUAUAUCCGUUACUAUCACAC-5′ (SEQ ID NO: 5013) LDHA-2131 Target:5′-CAACTGAATATAGGCAATGATAGTGTG-3′ (SEQ ID NO: 7027)5′-CUGAAUAUAGGCAAUGAUAGUGUgt-3′ (SEQ ID NO: 3000)3′-UUGACUUAUAUCCGUUACUAUCACACA-5′ (SEQ ID NO: 5014) LDHA-2132 Target:5′-AACTGAATATAGGCAATGATAGTGTGT-3′ (SEQ ID NO: 7028)5′-UGAAUAUAGGCAAUGAUAGUGUGtc-3′ (SEQ ID NO: 3001)3′-UGACUUAUAUCCGUUACUAUCACACAG-5′ (SEQ ID NO: 5015) LDHA-2133 Target:5′-ACTGAATATAGGCAATGATAGTGTGTC-3′ (SEQ ID NO: 7029)5′-GAAUAUAGGCAAUGAUAGUGUGUca-3′ (SEQ ID NO: 3002)3′-GACUUAUAUCCGUUACUAUCACACAGU-5′ (SEQ ID NO: 5016) LDHA-2134 Target:5′-CTGAATATAGGCAATGATAGTGTGTCA-3′ (SEQ ID NO: 7030)5′-AAUAUAGGCAAUGAUAGUGUGUCac-3′ (SEQ ID NO: 3003)3′-ACUUAUAUCCGUUACUAUCACACAGUG-5′ (SEQ ID NO: 5017) LDHA-2135 Target:5′-TGAATATAGGCAATGATAGTGTGTCAC-3′ (SEQ ID NO: 7031)5′-AUAUAGGCAAUGAUAGUGUGUCAct-3′ (SEQ ID NO: 3004)3′-CUUAUAUCCGUUACUAUCACACAGUGA-5′ (SEQ ID NO: 5018) LDHA-2136 Target:5′-GAATATAGGCAATGATAGTGTGTCACT-3′ (SEQ ID NO: 7032)5′-UAUAGGCAAUGAUAGUGUGUCACta-3′ (SEQ ID NO: 3005)3′-UUAUAUCCGUUACUAUCACACAGUGAU-5′ (SEQ ID NO: 5019) LDHA-2137 Target:5′-AATATAGGCAATGATAGTGTGTCACTA-3′ (SEQ ID NO: 7033)5′-AUAGGCAAUGAUAGUGUGUCACUat-3′ (SEQ ID NO: 3006)3′-UAUAUCCGUUACUAUCACACAGUGAUA-5′ (SEQ ID NO: 5020) LDHA-2138 Target:5′-ATATAGGCAATGATAGTGTGTCACTAT-3′ (SEQ ID NO: 7034)5′-UAGGCAAUGAUAGUGUGUCACUAta-3′ (SEQ ID NO: 3007)3′-AUAUCCGUUACUAUCACACAGUGAUAU-5′ (SEQ ID NO: 5021) LDHA-2139 Target:5′-TATAGGCAATGATAGTGTGTCACTATA-3′ (SEQ ID NO: 7035)5′-AGGCAAUGAUAGUGUGUCACUAUag-3′ (SEQ ID NO: 3008)3′-UAUCCGUUACUAUCACACAGUGAUAUC-5′ (SEQ ID NO: 5022) LDHA-2140 Target:5′-ATAGGCAATGATAGTGTGTCACTATAG-3′ (SEQ ID NO: 7036)5′-GGCAAUGAUAGUGUGUCACUAUAgg-3′ (SEQ ID NO: 3009)3′-AUCCGUUACUAUCACACAGUGAUAUCC-5′ (SEQ ID NO: 5023) LDHA-2141 Target:5′-TAGGCAATGATAGTGTGTCACTATAGG-3′ (SEQ ID NO: 7037)5′-GCAAUGAUAGUGUGUCACUAUAGgg-3′ (SEQ ID NO: 3010)3′-UCCGUUACUAUCACACAGUGAUAUCCC-5′ (SEQ ID NO: 5024) LDHA-2142 Target:5′-AGGCAATGATAGTGTGTCACTATAGGG-3′ (SEQ ID NO: 7038)5′-CAAUGAUAGUGUGUCACUAUAGGga-3′ (SEQ ID NO: 3011)3′-CCGUUACUAUCACACAGUGAUAUCCCU-5′ (SEQ ID NO: 5025) LDHA-2143 Target:5′-GGCAATGATAGTGTGTCACTATAGGGA-3′ (SEQ ID NO: 7039)5′-AAUGAUAGUGUGUCACUAUAGGGaa-3′ (SEQ ID NO: 3012)3′-CGUUACUAUCACACAGUGAUAUCCCUU-5′ (SEQ ID NO: 5026) LDHA-2144 Target:5′-GCAATGATAGTGTGTCACTATAGGGAA-3′ (SEQ ID NO: 7040)5′-AUGAUAGUGUGUCACUAUAGGGAac-3′ (SEQ ID NO: 3013)3′-GUUACUAUCACACAGUGAUAUCCCUUG-5′ (SEQ ID NO: 5027) LDHA-2145 Target:5′-CAATGATAGTGTGTCACTATAGGGAAC-3′ (SEQ ID NO: 7041)5′-UGAUAGUGUGUCACUAUAGGGAAca-3′ (SEQ ID NO: 3014)3′-UUACUAUCACACAGUGAUAUCCCUUGU-5′ (SEQ ID NO: 5028) LDHA-2146 Target:5′-AATGATAGTGTGTCACTATAGGGAACA-3′ (SEQ ID NO: 7042)5′-GAUAGUGUGUCACUAUAGGGAACac-3′ (SEQ ID NO: 3015)3′-UACUAUCACACAGUGAUAUCCCUUGUG-5′ (SEQ ID NO: 5029) LDHA-2147 Target:5′-ATGATAGTGTGTCACTATAGGGAACAC-3′ (SEQ ID NO: 7043)5′-AUAGUGUGUCACUAUAGGGAACAca-3′ (SEQ ID NO: 3016)3′-ACUAUCACACAGUGAUAUCCCUUGUGU-5′ (SEQ ID NO: 5030) LDHA-2148 Target:5′-TGATAGTGTGTCACTATAGGGAACACA-3′ (SEQ ID NO: 7044)5′-UAGUGUGUCACUAUAGGGAACACag-3′ (SEQ ID NO: 3017)3′-CUAUCACACAGUGAUAUCCCUUGUGUC-5′ (SEQ ID NO: 5031) LDHA-2149 Target:5′-GATAGTGTGTCACTATAGGGAACACAG-3′ (SEQ ID NO: 7045)5′-AGUGUGUCACUAUAGGGAACACAga-3′ (SEQ ID NO: 3018)3′-UAUCACACAGUGAUAUCCCUUGUGUCU-5′ (SEQ ID NO: 5032) LDHA-2150 Target:5′-ATAGTGTGTCACTATAGGGAACACAGA-3′ (SEQ ID NO: 7046)5′-GUGUGUCACUAUAGGGAACACAGat-3′ (SEQ ID NO: 3019)3′-AUCACACAGUGAUAUCCCUUGUGUCUA-5′ (SEQ ID NO: 5033) LDHA-2151 Target:5′-TAGTGTGTCACTATAGGGAACACAGAT-3′ (SEQ ID NO: 7047)5′-UGUGUCACUAUAGGGAACACAGAtt-3′ (SEQ ID NO: 3020)3′-UCACACAGUGAUAUCCCUUGUGUCUAA-5′ (SEQ ID NO: 5034) LDHA-2152 Target:5′-AGTGTGTCACTATAGGGAACACAGATT-3′ (SEQ ID NO: 7048)5′-GUGUCACUAUAGGGAACACAGAUtt-3′ (SEQ ID NO: 3021)3′-CACACAGUGAUAUCCCUUGUGUCUAAA-5′ (SEQ ID NO: 5035) LDHA-2153 Target:5′-GTGTGTCACTATAGGGAACACAGATTT-3′ (SEQ ID NO: 7049)5′-UGUCACUAUAGGGAACACAGAUUtt-3′ (SEQ ID NO: 3022)3′-ACACAGUGAUAUCCCUUGUGUCUAAAA-5′ (SEQ ID NO: 5036) LDHA-2154 Target:5′-TGTGTCACTATAGGGAACACAGATTTT-3′ (SEQ ID NO: 7050)5′-GUCACUAUAGGGAACACAGAUUUtt-3′ (SEQ ID NO: 3023)3′-CACAGUGAUAUCCCUUGUGUCUAAAAA-5′ (SEQ ID NO: 5037) LDHA-2155 Target:5′-GTGTCACTATAGGGAACACAGATTTTT-3′ (SEQ ID NO: 7051)5′-UCACUAUAGGGAACACAGAUUUUtg-3′ (SEQ ID NO: 3024)3′-ACAGUGAUAUCCCUUGUGUCUAAAAAC-5′ (SEQ ID NO: 5038) LDHA-2156 Target:5′-TGTCACTATAGGGAACACAGATTTTTG-3′ (SEQ ID NO: 7052)5′-CACUAUAGGGAACACAGAUUUUUga-3′ (SEQ ID NO: 3025)3′-CAGUGAUAUCCCUUGUGUCUAAAAACU-5′ (SEQ ID NO: 5039) LDHA-2157 Target:5′-GTCACTATAGGGAACACAGATTTTTGA-3′ (SEQ ID NO: 7053)5′-ACUAUAGGGAACACAGAUUUUUGag-3′ (SEQ ID NO: 3026)3′-AGUGAUAUCCCUUGUGUCUAAAAACUC-5′ (SEQ ID NO: 5040) LDHA-2158 Target:5′-TCACTATAGGGAACACAGATTTTTGAG-3′ (SEQ ID NO: 7054)5′-CUAUAGGGAACACAGAUUUUUGAga-3′ (SEQ ID NO: 3027)3′-GUGAUAUCCCUUGUGUCUAAAAACUCU-5′ (SEQ ID NO: 5041) LDHA-2159 Target:5′-CACTATAGGGAACACAGATTTTTGAGA-3′ (SEQ ID NO: 7055)5′-UAUAGGGAACACAGAUUUUUGAGat-3′ (SEQ ID NO: 3028)3′-UGAUAUCCCUUGUGUCUAAAAACUCUA-5′ (SEQ ID NO: 5042) LDHA-2160 Target:5′-ACTATAGGGAACACAGATTTTTGAGAT-3′ (SEQ ID NO: 7056)5′-AUAGGGAACACAGAUUUUUGAGAtc-3′ (SEQ ID NO: 3029)3′-GAUAUCCCUUGUGUCUAAAAACUCUAG-5′ (SEQ ID NO: 5043) LDHA-2161 Target:5′-CTATAGGGAACACAGATTTTTGAGATC-3′ (SEQ ID NO: 7057)5′-UAGGGAACACAGAUUUUUGAGAUct-3′ (SEQ ID NO: 3030)3′-AUAUCCCUUGUGUCUAAAAACUCUAGA-5′ (SEQ ID NO: 5044) LDHA-2162 Target:5′-TATAGGGAACACAGATTTTTGAGATCT-3′ (SEQ ID NO: 7058)5′-AGGGAACACAGAUUUUUGAGAUCtt-3′ (SEQ ID NO: 3031)3′-UAUCCCUUGUGUCUAAAAACUCUAGAA-5′ (SEQ ID NO: 5045) LDHA-2163 Target:5′-ATAGGGAACACAGATTTTTGAGATCTT-3′ (SEQ ID NO: 7059)5′-GGGAACACAGAUUUUUGAGAUCUtg-3′ (SEQ ID NO: 3032)3′-AUCCCUUGUGUCUAAAAACUCUAGAAC-5′ (SEQ ID NO: 5046) LDHA-2164 Target:5′-TAGGGAACACAGATTTTTGAGATCTTG-3′ (SEQ ID NO: 7060)5′-GGAACACAGAUUUUUGAGAUCUUgt-3′ (SEQ ID NO: 3033)3′-UCCCUUGUGUCUAAAAACUCUAGAACA-5′ (SEQ ID NO: 5047) LDHA-2165 Target:5′-AGGGAACACAGATTTTTGAGATCTTGT-3′ (SEQ ID NO: 7061)5′-GAACACAGAUUUUUGAGAUCUUGtc-3′ (SEQ ID NO: 3034)3′-CCCUUGUGUCUAAAAACUCUAGAACAG-5′ (SEQ ID NO: 5048) LDHA-2166 Target:5′-GGGAACACAGATTTTTGAGATCTTGTC-3′ (SEQ ID NO: 7062)5′-AACACAGAUUUUUGAGAUCUUGUcc-3′ (SEQ ID NO: 3035)3′-CCUUGUGUCUAAAAACUCUAGAACAGG-5′ (SEQ ID NO: 5049) LDHA-2167 Target:5′-GGAACACAGATTTTTGAGATCTTGTCC-3′ (SEQ ID NO: 7063)5′-ACACAGAUUUUUGAGAUCUUGUCct-3′ (SEQ ID NO: 3036)3′-CUUGUGUCUAAAAACUCUAGAACAGGA-5′ (SEQ ID NO: 5050) LDHA-2168 Target:5′-GAACACAGATTTTTGAGATCTTGTCCT-3′ (SEQ ID NO: 7064)5′-CACAGAUUUUUGAGAUCUUGUCCtc-3′ (SEQ ID NO: 3037)3′-UUGUGUCUAAAAACUCUAGAACAGGAG-5′ (SEQ ID NO: 5051) LDHA-2169 Target:5′-AACACAGATTTTTGAGATCTTGTCCTC-3′ (SEQ ID NO: 7065)5′-ACAGAUUUUUGAGAUCUUGUCCUct-3′ (SEQ ID NO: 3038)3′-UGUGUCUAAAAACUCUAGAACAGGAGA-5′ (SEQ ID NO: 5052) LDHA-2170 Target:5′-ACACAGATTTTTGAGATCTTGTCCTCT-3′ (SEQ ID NO: 7066)5′-CAGAUUUUUGAGAUCUUGUCCUCtg-3′ (SEQ ID NO: 3039)3′-GUGUCUAAAAACUCUAGAACAGGAGAC-5′ (SEQ ID NO: 5053) LDHA-2171 Target:5′-CACAGATTTTTGAGATCTTGTCCTCTG-3′ (SEQ ID NO: 7067)5′-AGAUUUUUGAGAUCUUGUCCUCUgg-3′ (SEQ ID NO: 3040)3′-UGUCUAAAAACUCUAGAACAGGAGACC-5′ (SEQ ID NO: 5054) LDHA-2172 Target:5′-ACAGATTTTTGAGATCTTGTCCTCTGG-3′ (SEQ ID NO: 7068)5′-GAUUUUUGAGAUCUUGUCCUCUGga-3′ (SEQ ID NO: 3041)3′-GUCUAAAAACUCUAGAACAGGAGACCU-5′ (SEQ ID NO: 5055) LDHA-2173 Target:5′-CAGATTTTTGAGATCTTGTCCTCTGGA-3′ (SEQ ID NO: 7069)5′-AUUUUUGAGAUCUUGUCCUCUGGaa-3′ (SEQ ID NO: 3042)3′-UCUAAAAACUCUAGAACAGGAGACCUU-5′ (SEQ ID NO: 5056) LDHA-2174 Target:5′-AGATTTTTGAGATCTTGTCCTCTGGAA-3′ (SEQ ID NO: 7070)5′-UUUUUGAGAUCUUGUCCUCUGGAag-3′ (SEQ ID NO: 3043)3′-CUAAAAACUCUAGAACAGGAGACCUUC-5′ (SEQ ID NO: 5057) LDHA-2175 Target:5′-GATTTTTGAGATCTTGTCCTCTGGAAG-3′ (SEQ ID NO: 7071)5′-UUUUGAGAUCUUGUCCUCUGGAAgc-3′ (SEQ ID NO: 3044)3′-UAAAAACUCUAGAACAGGAGACCUUCG-5′ (SEQ ID NO: 5058) LDHA-2176 Target:5′-ATTTTTGAGATCTTGTCCTCTGGAAGC-3′ (SEQ ID NO: 7072)5′-UUUGAGAUCUUGUCCUCUGGAAGct-3′ (SEQ ID NO: 3045)3′-AAAAACUCUAGAACAGGAGACCUUCGA-5′ (SEQ ID NO: 5059) LDHA-2177 Target:5′-TTTTTGAGATCTTGTCCTCTGGAAGCT-3′ (SEQ ID NO: 7073)5′-UUGAGAUCUUGUCCUCUGGAAGCtg-3′ (SEQ ID NO: 3046)3′-AAAACUCUAGAACAGGAGACCUUCGAC-5′ (SEQ ID NO: 5060) LDHA-2178 Target:5′-TTTTGAGATCTTGTCCTCTGGAAGCTG-3′ (SEQ ID NO: 7074)5′-UGAGAUCUUGUCCUCUGGAAGCUgg-3′ (SEQ ID NO: 3047)3′-AAACUCUAGAACAGGAGACCUUCGACC-5′ (SEQ ID NO: 5061) LDHA-2179 Target:5′-TTTGAGATCTTGTCCTCTGGAAGCTGG-3′ (SEQ ID NO: 7075)5′-GAGAUCUUGUCCUCUGGAAGCUGgt-3′ (SEQ ID NO: 3048)3′-AACUCUAGAACAGGAGACCUUCGACCA-5′ (SEQ ID NO: 5062) LDHA-2180 Target:5′-TTGAGATCTTGTCCTCTGGAAGCTGGT-3′ (SEQ ID NO: 7076)5′-AGAUCUUGUCCUCUGGAAGCUGGta-3′ (SEQ ID NO: 3049)3′-ACUCUAGAACAGGAGACCUUCGACCAU-5′ (SEQ ID NO: 5063) LDHA-2181 Target:5′-TGAGATCTTGTCCTCTGGAAGCTGGTA-3′ (SEQ ID NO: 7077)5′-GAUCUUGUCCUCUGGAAGCUGGUaa-3′ (SEQ ID NO: 3050)3′-CUCUAGAACAGGAGACCUUCGACCAUU-5′ (SEQ ID NO: 5064) LDHA-2182 Target:5′-GAGATCTTGTCCTCTGGAAGCTGGTAA-3′ (SEQ ID NO: 7078)5′-AUCUUGUCCUCUGGAAGCUGGUAac-3′ (SEQ ID NO: 3051)3′-UCUAGAACAGGAGACCUUCGACCAUUG-5′ (SEQ ID NO: 5065) LDHA-2183 Target:5′-AGATCTTGTCCTCTGGAAGCTGGTAAC-3′ (SEQ ID NO: 7079)5′-UCUUGUCCUCUGGAAGCUGGUAAca-3′ (SEQ ID NO: 3052)3′-CUAGAACAGGAGACCUUCGACCAUUGU-5′ (SEQ ID NO: 5066) LDHA-2184 Target:5′-GATCTTGTCCTCTGGAAGCTGGTAACA-3′ (SEQ ID NO: 7080)5′-CUUGUCCUCUGGAAGCUGGUAACaa-3′ (SEQ ID NO: 3053)3′-UAGAACAGGAGACCUUCGACCAUUGUU-5′ (SEQ ID NO: 5067) LDHA-2185 Target:5′-ATCTTGTCCTCTGGAAGCTGGTAACAA-3′ (SEQ ID NO: 7081)5′-UUGUCCUCUGGAAGCUGGUAACAat-3′ (SEQ ID NO: 3054)3′-AGAACAGGAGACCUUCGACCAUUGUUA-5′ (SEQ ID NO: 5068) LDHA-2186 Target:5′-TCTTGTCCTCTGGAAGCTGGTAACAAT-3′ (SEQ ID NO: 7082)5′-UGUCCUCUGGAAGCUGGUAACAAtt-3′ (SEQ ID NO: 3055)3′-GAACAGGAGACCUUCGACCAUUGUUAA-5′ (SEQ ID NO: 5069) LDHA-2187 Target:5′-CTTGTCCTCTGGAAGCTGGTAACAATT-3′ (SEQ ID NO: 7083)5′-GUCCUCUGGAAGCUGGUAACAAUta-3′ (SEQ ID NO: 3056)3′-AACAGGAGACCUUCGACCAUUGUUAAU-5′ (SEQ ID NO: 5070) LDHA-2188 Target:5′-TTGTCCTCTGGAAGCTGGTAACAATTA-3′ (SEQ ID NO: 7084)5′-UCCUCUGGAAGCUGGUAACAAUUaa-3′ (SEQ ID NO: 3057)3′-ACAGGAGACCUUCGACCAUUGUUAAUU-5′ (SEQ ID NO: 5071) LDHA-2189 Target:5′-TGTCCTCTGGAAGCTGGTAACAATTAA-3′ (SEQ ID NO: 7085)5′-CCUCUGGAAGCUGGUAACAAUUAaa-3′ (SEQ ID NO: 3058)3′-CAGGAGACCUUCGACCAUUGUUAAUUU-5′ (SEQ ID NO: 5072) LDHA-2190 Target:5′-GTCCTCTGGAAGCTGGTAACAATTAAA-3′ (SEQ ID NO: 7086)5′-CUCUGGAAGCUGGUAACAAUUAAaa-3′ (SEQ ID NO: 3059)3′-AGGAGACCUUCGACCAUUGUUAAUUUU-5′ (SEQ ID NO: 5073) LDHA-2191 Target:5′-TCCTCTGGAAGCTGGTAACAATTAAAA-3′ (SEQ ID NO: 7087)5′-UCUGGAAGCUGGUAACAAUUAAAaa-3′ (SEQ ID NO: 3060)3′-GGAGACCUUCGACCAUUGUUAAUUUUU-5′ (SEQ ID NO: 5074) LDHA-2192 Target:5′-CCTCTGGAAGCTGGTAACAATTAAAAA-3′ (SEQ ID NO: 7088)5′-CUGGAAGCUGGUAACAAUUAAAAac-3′ (SEQ ID NO: 3061)3′-GAGACCUUCGACCAUUGUUAAUUUUUG-5′ (SEQ ID NO: 5075) LDHA-2193 Target:5′-CTCTGGAAGCTGGTAACAATTAAAAAC-3′ (SEQ ID NO: 7089)5′-UGGAAGCUGGUAACAAUUAAAAAca-3′ (SEQ ID NO: 3062)3′-AGACCUUCGACCAUUGUUAAUUUUUGU-5′ (SEQ ID NO: 5076) LDHA-2194 Target:5′-TCTGGAAGCTGGTAACAATTAAAAACA-3′ (SEQ ID NO: 7090)5′-GGAAGCUGGUAACAAUUAAAAACaa-3′ (SEQ ID NO: 3063)3′-GACCUUCGACCAUUGUUAAUUUUUGUU-5′ (SEQ ID NO: 5077) LDHA-2195 Target:5′-CTGGAAGCTGGTAACAATTAAAAACAA-3′ (SEQ ID NO: 7091)5′-GAAGCUGGUAACAAUUAAAAACAat-3′ (SEQ ID NO: 3064)3′-ACCUUCGACCAUUGUUAAUUUUUGUUA-5′ (SEQ ID NO: 5078) LDHA-2196 Target:5′-TGGAAGCTGGTAACAATTAAAAACAAT-3′ (SEQ ID NO: 7092)5′-AAGCUGGUAACAAUUAAAAACAAtc-3′ (SEQ ID NO: 3065)3′-CCUUCGACCAUUGUUAAUUUUUGUUAG-5′ (SEQ ID NO: 5079) LDHA-2197 Target:5′-GGAAGCTGGTAACAATTAAAAACAATC-3′ (SEQ ID NO: 7093)5′-AGCUGGUAACAAUUAAAAACAAUct-3′ (SEQ ID NO: 3066)3′-CUUCGACCAUUGUUAAUUUUUGUUAGA-5′ (SEQ ID NO: 5080) LDHA-2198 Target:5′-GAAGCTGGTAACAATTAAAAACAATCT-3′ (SEQ ID NO: 7094)5′-GCUGGUAACAAUUAAAAACAAUCtt-3′ (SEQ ID NO: 3067)3′-UUCGACCAUUGUUAAUUUUUGUUAGAA-5′ (SEQ ID NO: 5081) LDHA-2199 Target:5′-AAGCTGGTAACAATTAAAAACAATCTT-3′ (SEQ ID NO: 7095)5′-CUGGUAACAAUUAAAAACAAUCUta-3′ (SEQ ID NO: 3068)3′-UCGACCAUUGUUAAUUUUUGUUAGAAU-5′ (SEQ ID NO: 5082) LDHA-2200 Target:5′-AGCTGGTAACAATTAAAAACAATCTTA-3′ (SEQ ID NO: 7096)5′-UGGUAACAAUUAAAAACAAUCUUaa-3′ (SEQ ID NO: 3069)3′-CGACCAUUGUUAAUUUUUGUUAGAAUU-5′ (SEQ ID NO: 5083) LDHA-2201 Target:5′-GCTGGTAACAATTAAAAACAATCTTAA-3′ (SEQ ID NO: 7097)5′-GGUAACAAUUAAAAACAAUCUUAag-3′ (SEQ ID NO: 3070)3′-GACCAUUGUUAAUUUUUGUUAGAAUUC-5′ (SEQ ID NO: 5084) LDHA-2202 Target:5′-CTGGTAACAATTAAAAACAATCTTAAG-3′ (SEQ ID NO: 7098)5′-GUAACAAUUAAAAACAAUCUUAAgg-3′ (SEQ ID NO: 3071)3′-ACCAUUGUUAAUUUUUGUUAGAAUUCC-5′ (SEQ ID NO: 5085) LDHA-2203 Target:5′-TGGTAACAATTAAAAACAATCTTAAGG-3′ (SEQ ID NO: 7099)5′-UAACAAUUAAAAACAAUCUUAAGgc-3′ (SEQ ID NO: 3072)3′-CCAUUGUUAAUUUUUGUUAGAAUUCCG-5′ (SEQ ID NO: 5086) LDHA-2204 Target:5′-GGTAACAATTAAAAACAATCTTAAGGC-3′ (SEQ ID NO: 7100)5′-AACAAUUAAAAACAAUCUUAAGGca-3′ (SEQ ID NO: 3073)3′-CAUUGUUAAUUUUUGUUAGAAUUCCGU-5′ (SEQ ID NO: 5087) LDHA-2205 Target:5′-GTAACAATTAAAAACAATCTTAAGGCA-3′ (SEQ ID NO: 7101)5′-ACAAUUAAAAACAAUCUUAAGGCag-3′ (SEQ ID NO: 3074)3′-AUUGUUAAUUUUUGUUAGAAUUCCGUC-5′ (SEQ ID NO: 5088) LDHA-2206 Target:5′-TAACAATTAAAAACAATCTTAAGGCAG-3′ (SEQ ID NO: 7102)5′-CAAUUAAAAACAAUCUUAAGGCAgg-3′ (SEQ ID NO: 3075)3′-UUGUUAAUUUUUGUUAGAAUUCCGUCC-5′ (SEQ ID NO: 5089) LDHA-2207 Target:5′-AACAATTAAAAACAATCTTAAGGCAGG-3′ (SEQ ID NO: 7103)5′-AAUUAAAAACAAUCUUAAGGCAGgg-3′ (SEQ ID NO: 3076)3′-UGUUAAUUUUUGUUAGAAUUCCGUCCC-5′ (SEQ ID NO: 5090) LDHA-2208 Target:5′-ACAATTAAAAACAATCTTAAGGCAGGG-3′ (SEQ ID NO: 7104)5′-AUUAAAAACAAUCUUAAGGCAGGga-3′ (SEQ ID NO: 3077)3′-GUUAAUUUUUGUUAGAAUUCCGUCCCU-5′ (SEQ ID NO: 5091) LDHA-2209 Target:5′-CAATTAAAAACAATCTTAAGGCAGGGA-3′ (SEQ ID NO: 7105)5′-UUAAAAACAAUCUUAAGGCAGGGaa-3′ (SEQ ID NO: 3078)3′-UUAAUUUUUGUUAGAAUUCCGUCCCUU-5′ (SEQ ID NO: 5092) LDHA-2210 Target:5′-AATTAAAAACAATCTTAAGGCAGGGAA-3′ (SEQ ID NO: 7106)5′-UAAAAACAAUCUUAAGGCAGGGAaa-3′ (SEQ ID NO: 3079)3′-UAAUUUUUGUUAGAAUUCCGUCCCUUU-5′ (SEQ ID NO: 5093) LDHA-2211 Target:5′-ATTAAAAACAATCTTAAGGCAGGGAAA-3′ (SEQ ID NO: 7107)5′-AAAAACAAUCUUAAGGCAGGGAAaa-3′ (SEQ ID NO: 3080)3′-AAUUUUUGUUAGAAUUCCGUCCCUUUU-5′ (SEQ ID NO: 5094) LDHA-2212 Target:5′-TTAAAAACAATCTTAAGGCAGGGAAAA-3′ (SEQ ID NO: 7108)5′-AAAACAAUCUUAAGGCAGGGAAAaa-3′ (SEQ ID NO: 3081)3′-AUUUUUGUUAGAAUUCCGUCCCUUUUU-5′ (SEQ ID NO: 5095) LDHA-2213 Target:5′-TAAAAACAATCTTAAGGCAGGGAAAAA-3′ (SEQ ID NO: 7109)5′-AAACAAUCUUAAGGCAGGGAAAAaa-3′ (SEQ ID NO: 3082)3′-UUUUUGUUAGAAUUCCGUCCCUUUUUU-5′ (SEQ ID NO: 5096) LDHA-2214 Target:5′-AAAAACAATCTTAAGGCAGGGAAAAAA-3′ (SEQ ID NO: 7110)5′-AACAAUCUUAAGGCAGGGAAAAAaa-3′ (SEQ ID NO: 3083)3′-UUUUGUUAGAAUUCCGUCCCUUUUUUU-5′ (SEQ ID NO: 5097) LDHA-2215 Target:5′-AAAACAATCTTAAGGCAGGGAAAAAAA-3′ (SEQ ID NO: 7111)5′-ACAAUCUUAAGGCAGGGAAAAAAaa-3′ (SEQ ID NO: 3084)3′-UUUGUUAGAAUUCCGUCCCUUUUUUUU-5′ (SEQ ID NO: 5098) LDHA-2216 Target:5′-AAACAATCTTAAGGCAGGGAAAAAAAA-3′ (SEQ ID NO: 7112)5′-CAAUCUUAAGGCAGGGAAAAAAAaa-3′ (SEQ ID NO: 3085)3′-UUGUUAGAAUUCCGUCCCUUUUUUUUU-5′ (SEQ ID NO: 5099) LDHA-2217 Target:5′-AACAATCTTAAGGCAGGGAAAAAAAAA-3′ (SEQ ID NO: 7113)5′-AAUCUUAAGGCAGGGAAAAAAAAaa-3′ (SEQ ID NO: 3086)3′-UGUUAGAAUUCCGUCCCUUUUUUUUUU-5′ (SEQ ID NO: 5100) LDHA-2218 Target:5′-ACAATCTTAAGGCAGGGAAAAAAAAAA-3′ (SEQ ID NO: 7114)5′-AUCUUAAGGCAGGGAAAAAAAAAaa-3′ (SEQ ID NO: 3087)3′-GUUAGAAUUCCGUCCCUUUUUUUUUUU-5′ (SEQ ID NO: 5101) LDHA-2219 Target:5′-CAATCTTAAGGCAGGGAAAAAAAAAAA-3′ (SEQ ID NO: 7115)5′-UCUUAAGGCAGGGAAAAAAAAAAaa-3′ (SEQ ID NO: 3088)3′-UUAGAAUUCCGUCCCUUUUUUUUUUUU-5′ (SEQ ID NO: 5102) LDHA-2220 Target:5′-AATCTTAAGGCAGGGAAAAAAAAAAAA-3′ (SEQ ID NO: 7116)5′-CUUAAGGCAGGGAAAAAAAAAAAaa-3′ (SEQ ID NO: 3089)3′-UAGAAUUCCGUCCCUUUUUUUUUUUUU-5′ (SEQ ID NO: 5103) LDHA-2221 Target:5′-ATCTTAAGGCAGGGAAAAAAAAAAAAA-3′ (SEQ ID NO: 7117)5′-UUAAGGCAGGGAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3090)3′-AGAAUUCCGUCCCUUUUUUUUUUUUUU-5′ (SEQ ID NO: 5104) LDHA-2222 Target:5′-TCTTAAGGCAGGGAAAAAAAAAAAAAA-3′ (SEQ ID NO: 7118)5′-UAAGGCAGGGAAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3091)3′-GAAUUCCGUCCCUUUUUUUUUUUUUUU-5′ (SEQ ID NO: 5105) LDHA-2223 Target:5′-CTTAAGGCAGGGAAAAAAAAAAAAAAA-3′ (SEQ ID NO: 7119)5′-AAGGCAGGGAAAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3092)3′-AAUUCCGUCCCUUUUUUUUUUUUUUUU-5′ (SEQ ID NO: 5106) LDHA-2224 Target:5′-TTAAGGCAGGGAAAAAAAAAAAAAAAA-3′ (SEQ ID NO: 7120)5′-AGGCAGGGAAAAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3093)3′-AUUCCGUCCCUUUUUUUUUUUUUUUUU-5′ (SEQ ID NO: 5107) LDHA-2225 Target:5′-TAAGGCAGGGAAAAAAAAAAAAAAAAA-3′ (SEQ ID NO: 7121)5′-GGCAGGGAAAAAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3094)3′-UUCCGUCCCUUUUUUUUUUUUUUUUUU-5′ (SEQ ID NO: 5108) LDHA-2226 Target:5′-AAGGCAGGGAAAAAAAAAAAAAAAAAA-3′ (SEQ ID NO: 7122)

Within Tables 2, 3, 5, 7, 8, 10 and 12 above, underlined residuesindicate 2′-O-methyl residues, UPPER CASE indicates ribonucleotides, andlower case denotes deoxyribonucleotides. The DsiRNA agents of Tables2-3, 7-8 and 12 above are 25/27mer agents possessing a blunt end. Thestructures and/or modification patterning of the agents of Tables 2-3,7-8 and 12 above can be readily adapted to the above generic sequencestructures, e.g., the 3′ overhang of the second strand can be extendedor contracted, 2′-O-methylation of the second strand can be expandedtowards the 5′ end of the second strand, optionally at alternatingsites, etc. Such further modifications are optional, as 25/27mer DsiRNAswith such modifications can also be readily designed from the aboveDsiRNA agents and are also expected to be functional inhibitors oflactate dehydrogenase expression. Similarly, the 27mer “blunt/blunt”DsiRNA structures and/or modification patterns of the agents of Tables 5and 10 above can also be readily adapted to the above generic sequencestructures, e.g., for application of modification patterning of theantisense strand to such structures and/or adaptation of such sequencesto the above generic structures.

In certain embodiments, 27mer DsiRNAs possessing independent strandlengths each of 27 nucleotides are designed and synthesized fortargeting of the same sites within the lactate dehydrogenase transcriptas the asymmetric “25/27” structures shown in Tables 2-3, 7-8 and 12herein. Exemplary “27/27” DsiRNAs are optionally designed with a“blunt/blunt” structure as shown for the DsiRNAs of Tables 5 and 10above.

In certain embodiments, the dsRNA agents of the invention require, e.g.,at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25 or at least 26 residues of the first strand to becomplementary to corresponding residues of the second strand. In certainrelated embodiments, these first strand residues complementary tocorresponding residues of the second strand are optionally consecutiveresidues.

In certain DsiRNAmm (“DsiRNA mismatch”) embodiments of the instantinvention, mismatched base pairs are located within a “mismatch-tolerantregion” which is defined herein with respect to the location of theprojected Ago2 cut site of the corresponding target nucleic acid. Themismatch tolerant region is located “upstream of” the projected Ago2 cutsite of the target strand. “Upstream” in this context will be understoodas the 5′-most portion of the DsiRNAmm duplex, where 5′ refers to theorientation of the sense strand of the DsiRNA duplex. Therefore, themismatch tolerant region is upstream of the base on the sense(passenger) strand that corresponds to the projected Ago2 cut site ofthe target nucleic acid (see FIG. 1); alternatively, when referring tothe antisense (guide) strand of the DsiRNAmm, the mismatch tolerantregion can also be described as positioned downstream of the base thatis complementary to the projected Ago2 cut site of the target nucleicacid, that is, the 3′-most portion of the antisense strand of theDsiRNAmm (where position 1 of the antisense strand is the 5′ terminalnucleotide of the antisense strand, see FIG. 1).

In one embodiment, for example with numbering as depicted in FIG. 1, themismatch tolerant region is positioned between and including base pairs3-9 when numbered from the nucleotide starting at the 5′ end of thesense strand of the duplex. Therefore, a DsiRNAmm of the inventionpossesses a single mismatched base pair at any one of positions 3, 4, 5,6, 7, 8 or 9 of the sense strand of a right-hand extended DsiRNA (whereposition 1 is the 5′ terminal nucleotide of the sense strand andposition 9 is the nucleotide residue of the sense strand that isimmediately 5′ of the projected Ago2 cut site of the target lactatedehydrogenase RNA sequence corresponding to the sense strand sequence).In certain embodiments, for a DsiRNAmm that possesses a mismatched basepair nucleotide at any of positions 3, 4, 5, 6, 7, 8 or 9 of the sensestrand, the corresponding mismatched base pair nucleotide of theantisense strand not only forms a mismatched base pair with the DsiRNAmmsense strand sequence, but also forms a mismatched base pair with aDsiRNAmm target lactate dehydrogenase RNA sequence (thus,complementarity between the antisense strand sequence and the sensestrand sequence is disrupted at the mismatched base pair within theDsiRNAmm, and complementarity is similarly disrupted between theantisense strand sequence of the DsiRNAmm and the target lactatedehydrogenase RNA sequence). In alternative embodiments, the mismatchbase pair nucleotide of the antisense strand of a DsiRNAmm only form amismatched base pair with a corresponding nucleotide of the sense strandsequence of the DsiRNAmm, yet base pairs with its corresponding targetlactate dehydrogenase RNA sequence nucleotide (thus, complementaritybetween the antisense strand sequence and the sense strand sequence isdisrupted at the mismatched base pair within the DsiRNAmm, yetcomplementarity is maintained between the antisense strand sequence ofthe DsiRNAmm and the target lactate dehydrogenase RNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region (mismatch region) as described above(e.g., a DsiRNAmm harboring a mismatched nucleotide residue at any oneof positions 3, 4, 5, 6, 7, 8 or 9 of the sense strand) can furtherinclude one, two or even three additional mismatched base pairs. Inpreferred embodiments, these one, two or three additional mismatchedbase pairs of the DsiRNAmm occur at position(s) 3, 4, 5, 6, 7, 8 and/or9 of the sense strand (and at corresponding residues of the antisensestrand). In one embodiment where one additional mismatched base pair ispresent within a DsiRNAmm, the two mismatched base pairs of the sensestrand can occur, e.g., at nucleotides of both position 4 and position 6of the sense strand (with mismatch also occurring at correspondingnucleotide residues of the antisense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that base pair with theantisense strand sequence (e.g., for a DsiRNAmm possessing mismatchednucleotides at positions 3 and 6, but not at positions 4 and 5, themismatched residues of sense strand positions 3 and 6 are interspersedby two nucleotides that form matched base pairs with correspondingresidues of the antisense strand). For example, two residues of thesense strand (located within the mismatch-tolerant region of the sensestrand) that form mismatched base pairs with the corresponding antisensestrand sequence can occur with zero, one, two, three, four or fivematched base pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 4 and 8, but not at positions 5,6 and 7, the mismatched residues of sense strand positions 3 and 4 areadjacent to one another, while the mismatched residues of sense strandpositions 4 and 8 are interspersed by three nucleotides that formmatched base pairs with corresponding residues of the antisense strand).For example, three residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two, three or four matched base pairs located between any twoof these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along thesense strand nucleotide sequence). Alternatively, nucleotides of thesense strand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 5, 7 and 8, but not at positions4 and 6, the mismatched residues of sense strand positions 7 and 8 areadjacent to one another, while the mismatched residues of sense strandpositions 3 and 5 are interspersed by one nucleotide that forms amatched base pair with the corresponding residue of the antisensestrand—similarly, the mismatched residues of sense strand positions 5and 7 are also interspersed by one nucleotide that forms a matched basepair with the corresponding residue of the antisense strand). Forexample, four residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two or three matched base pairs located between any two ofthese mismatched base pairs.

In another embodiment, for example with numbering also as depicted inFIG. 1, a DsiRNAmm of the invention comprises a mismatch tolerant regionwhich possesses a single mismatched base pair nucleotide at any one ofpositions 17, 18, 19, 20, 21, 22 or 23 of the antisense strand of theDsiRNA (where position 1 is the 5′ terminal nucleotide of the antisensestrand and position 17 is the nucleotide residue of the antisense strandthat is immediately 3′ (downstream) in the antisense strand of theprojected Ago2 cut site of the target lactate dehydrogenase RNA sequencesufficiently complementary to the antisense strand sequence). In certainembodiments, for a DsiRNAmm that possesses a mismatched base pairnucleotide at any of positions 17, 18, 19, 20, 21, 22 or 23 of theantisense strand with respect to the sense strand of the DsiRNAmm, themismatched base pair nucleotide of the antisense strand not only forms amismatched base pair with the DsiRNAmm sense strand sequence, but alsoforms a mismatched base pair with a DsiRNAmm target lactatedehydrogenase RNA sequence (thus, complementarity between the antisensestrand sequence and the sense strand sequence is disrupted at themismatched base pair within the DsiRNAmm, and complementarity issimilarly disrupted between the antisense strand sequence of theDsiRNAmm and the target lactate dehydrogenase RNA sequence). Inalternative embodiments, the mismatch base pair nucleotide of theantisense strand of a DsiRNAmm only forms a mismatched base pair with acorresponding nucleotide of the sense strand sequence of the DsiRNAmm,yet base pairs with its corresponding target lactate dehydrogenase RNAsequence nucleotide (thus, complementarity between the antisense strandsequence and the sense strand sequence is disrupted at the mismatchedbase pair within the DsiRNAmm, yet complementarity is maintained betweenthe antisense strand sequence of the DsiRNAmm and the target lactatedehydrogenase RNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region as described above (e.g., a DsiRNAmmharboring a mismatched nucleotide residue at positions 17, 18, 19, 20,21, 22 or 23 of the antisense strand) can further include one, two oreven three additional mismatched base pairs. In preferred embodiments,these one, two or three additional mismatched base pairs of the DsiRNAmmoccur at position(s) 17, 18, 19, 20, 21, 22 and/or 23 of the antisensestrand (and at corresponding residues of the sense strand). In oneembodiment where one additional mismatched base pair is present within aDsiRNAmm, the two mismatched base pairs of the antisense strand canoccur, e.g., at nucleotides of both position 18 and position 20 of theantisense strand (with mismatch also occurring at correspondingnucleotide residues of the sense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the antisensestrand nucleotide sequence). Alternatively, nucleotides of the antisensestrand that form mismatched base pairs with the sense strand sequencecan be interspersed by nucleotides that base pair with the sense strandsequence (e.g., for a DsiRNAmm possessing mismatched nucleotides atpositions 17 and 20, but not at positions 18 and 19, the mismatchedresidues of antisense strand positions 17 and 20 are interspersed by twonucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, two residues of the antisense strand(located within the mismatch-tolerant region of the sense strand) thatform mismatched base pairs with the corresponding sense strand sequencecan occur with zero, one, two, three, four, five, six or seven matchedbase pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 17, 18 and 22, but not at positions19, 20 and 21, the mismatched residues of antisense strand positions 17and 18 are adjacent to one another, while the mismatched residues ofantisense strand positions 18 and 122 are interspersed by threenucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, three residues of the antisense strand(located within the mismatch-tolerant region of the antisense strand)that form mismatched base pairs with the corresponding sense strandsequence can occur with zero, one, two, three, four, five or six matchedbase pairs located between any two of these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 18, 20, 22 and 23, but not atpositions 19 and 21, the mismatched residues of antisense strandpositions 22 and 23 are adjacent to one another, while the mismatchedresidues of antisense strand positions 18 and 20 are interspersed by onenucleotide that forms a matched base pair with the corresponding residueof the sense strand—similarly, the mismatched residues of antisensestrand positions 20 and 22 are also interspersed by one nucleotide thatforms a matched base pair with the corresponding residue of the sensestrand). For example, four residues of the antisense strand (locatedwithin the mismatch-tolerant region of the antisense strand) that formmismatched base pairs with the corresponding sense strand sequence canoccur with zero, one, two, three, four or five matched base pairslocated between any two of these mismatched base pairs.

For reasons of clarity, the location(s) of mismatched nucleotideresidues within the above DsiRNAmm agents are numbered in reference tothe 5′ terminal residue of either sense or antisense strands of theDsiRNAmm. The numbering of positions located within themismatch-tolerant region (mismatch region) of the antisense strand canshift with variations in the proximity of the 5′ terminus of the senseor antisense strand to the projected Ago2 cleavage site. Thus, thelocation(s) of preferred mismatch sites within either antisense strandor sense strand can also be identified as the permissible proximity ofsuch mismatches to the projected Ago2 cut site. Accordingly, in onepreferred embodiment, the position of a mismatch nucleotide of the sensestrand of a DsiRNAmm is the nucleotide residue of the sense strand thatis located immediately 5′ (upstream) of the projected Ago2 cleavage siteof the corresponding target lactate dehydrogenase RNA sequence. In otherpreferred embodiments, a mismatch nucleotide of the sense strand of aDsiRNAmm is positioned at the nucleotide residue of the sense strandthat is located two nucleotides 5′ (upstream) of the projected Ago2cleavage site, three nucleotides 5′ (upstream) of the projected Ago2cleavage site, four nucleotides 5′ (upstream) of the projected Ago2cleavage site, five nucleotides 5′ (upstream) of the projected Ago2cleavage site, six nucleotides 5′ (upstream) of the projected Ago2cleavage site, seven nucleotides 5′ (upstream) of the projected Ago2cleavage site, eight nucleotides 5′ (upstream) of the projected Ago2cleavage site, or nine nucleotides 5′ (upstream) of the projected Ago2cleavage site.

Exemplary single mismatch-containing 25/27mer DsiRNAs (DsiRNAmm) includethe following structures (such mismatch-containing structures may alsobe incorporated into other exemplary DsiRNA structures shown herein).

5′-XX^(M)XXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXX_(M)XXXXXXXXXXXXXXXXXXXXXX-5′5′-XXX^(M)XXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXX_(M)XXXXXXXXXXXXXXXXXXXXX-5′5′-XXXX^(M)XXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXX_(M)XXXXXXXXXXXXXXXXXXXX-5′5′-XXXXX^(M)XXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXX_(M)XXXXXXXXXXXXXXXXXXX-5′5′-XXXXXX^(M)XXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXX_(M)XXXXXXXXXXXXXXXXXX-5′5′-XXXXXXX^(M)XXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXX_(M)XXXXXXXXXXXXXXXXX-5′5′-XXXXXXXX^(M)XXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXX_(M)XXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “M”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “M” residues of otherwise complementary strandwhen strands are annealed. Any of the residues of such agents canoptionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above, can also be used in theabove DsiRNAmm agents. For the above mismatch structures, the top strandis the sense strand, and the bottom strand is the antisense strand.

In certain embodiments, a DsiRNA of the invention can contain mismatchesthat exist in reference to the target lactate dehydrogenase RNA sequenceyet do not necessarily exist as mismatched base pairs within the twostrands of the DsiRNA—thus, a DsiRNA can possess perfect complementaritybetween first and second strands of a DsiRNA, yet still possessmismatched residues in reference to a target lactate dehydrogenase RNA(which, in certain embodiments, may be advantageous in promotingefficacy and/or potency and/or duration of effect). In certainembodiments, where mismatches occur between antisense strand and targetlactate dehydrogenase RNA sequence, the position of a mismatch islocated within the antisense strand at a position(s) that corresponds toa sequence of the sense strand located 5′ of the projected Ago2 cut siteof the target region—e.g., antisense strand residue(s) positioned withinthe antisense strand to the 3′ of the antisense residue which iscomplementary to the projected Ago2 cut site of the target sequence.

Exemplary 25/27mer DsiRNAs that harbor a single mismatched residue inreference to target sequences include the following structures.

Target RNA Sequence: 5′- . . . AXXXXXXXXXXXXXXXXXXXX . . . -3′ DsiRNAmmSense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-EXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XAXXXXXXXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XEXXXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .AXXXXXXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-BXXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXEXXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XAXXXXXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XBXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXEXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXAXXXXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXBXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXEXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXXAXXXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXBXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXEXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXXXAXXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXXBXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXEXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXXXXAXXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXXXBXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXEXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXXXXXAXXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXXXXBXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXXEXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXXXXXXAXXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXXXXXBXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXXXEXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence: 5′- . . .XXXXXXXXAXXXXXXXXXX . . . -3′ DsiRNAmm Sense Strand:5′-XXXXXXXXBXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXXXXEXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “E”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “A” RNA residues of otherwise complementary(target) strand when strands are annealed, yet optionally do base pairwith corresponding “B” residues (“B” residues are also RNA, DNA ornon-natural or modified nucleic acids). Any of the residues of suchagents can optionally be 2′-O-methyl RNA monomers—alternatingpositioning of 2′-O-methyl RNA monomers that commences from the3′-terminal residue of the bottom (second) strand, as shown above, canalso be used in the above DsiRNA agents.

In certain embodiments, the guide strand of a dsRNA of the inventionthat is sufficiently complementary to a target RNA (e.g., mRNA) along atleast 19 nucleotides of the target gene sequence to reduce target geneexpression is not perfectly complementary to the at least 19 nucleotidelong target gene sequence. Rather, it is appreciated that the guidestrand of a dsRNA of the invention that is sufficiently complementary toa target mRNA along at least 19 nucleotides of a target RNA sequence toreduce target gene expression can have one, two, three, or even four ormore nucleotides that are mismatched with the 19 nucleotide or longertarget strand sequence. Thus, for a 19 nucleotide target RNA sequence,the guide strand of a dsRNA of the invention can be sufficientlycomplementary to the target RNA sequence to reduce target gene levelswhile possessing, e.g., only 15/19, 16/19, 17/19 or 18/19 matchednucleotide residues between guide strand and target RNA sequence.

In addition to the above-exemplified structures, dsRNAs of the inventioncan also possess one, two or three additional residues that form furthermismatches with the target lactate dehydrogenase RNA sequence. Suchmismatches can be consecutive, or can be interspersed by nucleotidesthat form matched base pairs with the target lactate dehydrogenase RNAsequence. Where interspersed by nucleotides that form matched basepairs, mismatched residues can be spaced apart from each other within asingle strand at an interval of one, two, three, four, five, six, sevenor even eight base paired nucleotides between such mismatch-formingresidues.

As for the above-described DsiRNAmm agents, a preferred location withindsRNAs (e.g., DsiRNAs) for antisense strand nucleotides that formmismatched base pairs with target lactate dehydrogenase RNA sequence(yet may or may not form mismatches with corresponding sense strandnucleotides) is within the antisense strand region that is located 3′(downstream) of the antisense strand sequence which is complementary tothe projected Ago2 cut site of the DsiRNA (e.g., in FIG. 1, the regionof the antisense strand which is 3′ of the projected Ago2 cut site ispreferred for mismatch-forming residues and happens to be located atpositions 17-23 of the antisense strand for the 25/27mer agent shown inFIG. 1). Thus, in one embodiment, the position of a mismatch nucleotide(in relation to the target lactate dehydrogenase RNA sequence) of theantisense strand of a DsiRNAmm is the nucleotide residue of theantisense strand that is located immediately 3′ (downstream) within theantisense strand sequence of the projected Ago2 cleavage site of thecorresponding target lactate dehydrogenase RNA sequence. In otherpreferred embodiments, a mismatch nucleotide of the antisense strand ofa DsiRNAmm (in relation to the target lactate dehydrogenase RNAsequence) is positioned at the nucleotide residue of the antisensestrand that is located two nucleotides 3′ (downstream) of thecorresponding projected Ago2 cleavage site, three nucleotides 3′(downstream) of the corresponding projected Ago2 cleavage site, fournucleotides 3′ (downstream) of the corresponding projected Ago2 cleavagesite, five nucleotides 3′ (downstream) of the corresponding projectedAgo2 cleavage site, six nucleotides 3′ (downstream) of the projectedAgo2 cleavage site, seven nucleotides 3′ (downstream) of the projectedAgo2 cleavage site, eight nucleotides 3′ (downstream) of the projectedAgo2 cleavage site, or nine nucleotides 3′ (downstream) of the projectedAgo2 cleavage site.

In dsRNA agents possessing two mismatch-forming nucleotides of theantisense strand (where mismatch-forming nucleotides are mismatchforming in relation to target lactate dehydrogenase RNA sequence),mismatches can occur consecutively (e.g., at consecutive positions alongthe antisense strand nucleotide sequence). Alternatively, nucleotides ofthe antisense strand that form mismatched base pairs with the targetlactate dehydrogenase RNA sequence can be interspersed by nucleotidesthat base pair with the target lactate dehydrogenase RNA sequence (e.g.,for a DsiRNA possessing mismatch-forming nucleotides at positions 17 and20 (starting from the 5′ terminus (position 1) of the antisense strandof the 25/27mer agent shown in FIG. 1), but not at positions 18 and 19,the mismatched residues of sense strand positions 17 and 20 areinterspersed by two nucleotides that form matched base pairs withcorresponding residues of the target lactate dehydrogenase RNAsequence). For example, two residues of the antisense strand (locatedwithin the mismatch-tolerant region of the antisense strand) that formmismatched base pairs with the corresponding target lactatedehydrogenase RNA sequence can occur with zero, one, two, three, four orfive matched base pairs (with respect to target lactate dehydrogenaseRNA sequence) located between these mismatch-forming base pairs.

For certain dsRNAs possessing three mismatch-forming base pairs(mismatch-forming with respect to target lactate dehydrogenase RNAsequence), mismatch-forming nucleotides can occur consecutively (e.g.,in a triplet along the antisense strand nucleotide sequence).Alternatively, nucleotides of the antisense strand that form mismatchedbase pairs with the target lactate dehydrogenase RNA sequence can beinterspersed by nucleotides that form matched base pairs with the targetlactate dehydrogenase RNA sequence (e.g., for a DsiRNA possessingmismatched nucleotides at positions 17, 18 and 22, but not at positions19, 20 and 21, the mismatch-forming residues of antisense strandpositions 17 and 18 are adjacent to one another, while themismatch-forming residues of antisense strand positions 18 and 22 areinterspersed by three nucleotides that form matched base pairs withcorresponding residues of the target lactate dehydrogenase RNA). Forexample, three residues of the antisense strand (located within themismatch-tolerant region of the antisense strand) that form mismatchedbase pairs with the corresponding target lactate dehydrogenase RNAsequence can occur with zero, one, two, three or four matched base pairslocated between any two of these mismatch-forming base pairs.

For certain dsRNAs possessing four mismatch-forming base pairs(mismatch-forming with respect to target lactate dehydrogenase RNAsequence), mismatch-forming nucleotides can occur consecutively (e.g.,in a quadruplet along the sense strand nucleotide sequence).Alternatively, nucleotides of the antisense strand that form mismatchedbase pairs with the target lactate dehydrogenase RNA sequence can beinterspersed by nucleotides that form matched base pairs with the targetlactate dehydrogenase RNA sequence (e.g., for a DsiRNA possessingmismatch-forming nucleotides at positions 17, 19, 21 and 22, but not atpositions 18 and 20, the mismatch-forming residues of antisense strandpositions 21 and 22 are adjacent to one another, while themismatch-forming residues of antisense strand positions 17 and 19 areinterspersed by one nucleotide that forms a matched base pair with thecorresponding residue of the target lactate dehydrogenase RNAsequence—similarly, the mismatch-forming residues of antisense strandpositions 19 and 21 are also interspersed by one nucleotide that forms amatched base pair with the corresponding residue of the target lactatedehydrogenase RNA sequence). For example, four residues of the antisensestrand (located within the mismatch-tolerant region of the antisensestrand) that form mismatched base pairs with the corresponding targetlactate dehydrogenase RNA sequence can occur with zero, one, two orthree matched base pairs located between any two of thesemismatch-forming base pairs.

The above DsiRNAmm and other dsRNA structures are described in order toexemplify certain structures of DsiRNAmm and dsRNA agents. Design of theabove DsiRNAmm and dsRNA structures can be adapted to generate, e.g.,DsiRNAmm forms of other DsiRNA structures shown infra. As exemplifiedabove, dsRNAs can also be designed that possess single mismatches (ortwo, three or four mismatches) between the antisense strand of the dsRNAand a target sequence, yet optionally can retain perfect complementaritybetween sense and antisense strand sequences of a dsRNA.

It is further noted that the dsRNA agents exemplified infra can alsopossess insertion/deletion (in/del) structures within theirdouble-stranded and/or target lactate dehydrogenase RNA-alignedstructures. Accordingly, the dsRNAs of the invention can be designed topossess in/del variations in, e.g., antisense strand sequence ascompared to target lactate dehydrogenase RNA sequence and/or antisensestrand sequence as compared to sense strand sequence, with preferredlocation(s) for placement of such in/del nucleotides corresponding tothose locations described above for positioning of mismatched and/ormismatch-forming base pairs.

It is also noted that the DsiRNAs of the instant invention can toleratemismatches within the 3′-terminal region of the sense strand/5′-terminalregion of the antisense strand, as this region is modeled to beprocessed by Dicer and liberated from the guide strand sequence thatloads into RISC. Exemplary DsiRNA structures of the invention thatharbor such mismatches include the following:

Target RNA Sequence: 5′- . . . XXXXXXXXXXXXXXXXXXXXXHXXX . . . -3′DsiRNA Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXIXDD-3′ DsiRNA AntisenseStrand: 3′-XXXXXXXXXXXXXXXXXXXXXXXJXXX-5′ Target RNA Sequence: 5′- . . .XXXXXXXXXXXXXXXXXXXXXXHXX . . . -3′ DsiRNA Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXIDD-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXXJXX-5′ Target RNA Sequence: 5′- . . .XXXXXXXXXXXXXXXXXXXXXXXHX . . . -3′ DsiRNA Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXXID-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXXXJX-5′ Target RNA Sequence: 5′- . . .XXXXXXXXXXXXXXXXXXXXXXXXH . . . -3′ DsiRNA Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXXDI-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXXXXJ-5′wherein “X”=RNA, “D”=DNA and “r” and “J”=Nucleic acid residues (RNA, DNAor non-natural or modified nucleic acids) that do not base pair(hydrogen bond) with one another, yet optionally “J” is complementary totarget RNA sequence nucleotide “H”. Any of the residues of such agentscan optionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above—or any of the above-describedmethylation patterns—can also be used in the above DsiRNA agents. Theabove mismatches can also be combined within the DsiRNAs of the instantinvention.In the below exemplary structures, such mismatches are introduced withinthe asymmetric LDHA-1287 DsiRNA (newly-introduced mismatch residues areitalicized):LDHA-1287 25/27mer DsiRNA, mismatch position=19 of sense strand (from5′-terminus)

(SEQ ID NO: 7127) 5′-CAAUUUUAAAGUCUUCUG^(U)UGUCat-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGAC_(U)ACAGUA-5′Optionally, the mismatched ‘U’ residue of position 19 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=20 of sense strand (from5′-terminus)

(SEQ ID NO: 7128) 5′-CAAUUUUAAAGUCUUCUGA^(A)GUCat-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGACU_(A)CAGUA-5′Optionally, the mismatched ‘A’ residue of position 20 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=21 of sense strand (from5′-terminus)

(SEQ ID NO: 7129) 5′-CAAUUUUAAAGUCUUCUGAU^(A)UCat-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGACUA_(C)AGUA-5′Optionally, the mismatched ‘A’ residue of position 21 of the sensestrand is alternatively ‘U’ or ‘C’.LDHA-1287 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

(SEQ ID NO: 7130) 5′-CAAUUUUAAAGUCUUCUGAUG^(G)Cat-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGACUAC_(A)GUA-5′Optionally, the mismatched ‘G’ residue of position 22 of the sensestrand is alternatively ‘A’ or ‘C’.LDHA-1287 25/27mer DsiRNA, mismatch position=23 of sense strand (from5′-terminus)

(SEQ ID NO: 7131) 5′-CAAUUUUAAAGUCUUCUGAUGU^(A)at-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGACUACA_(G)UA-5′Optionally, the mismatched ‘A’ residue of position 23 of the sensestrand is alternatively ‘U’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=24 of sense strand (from5′-terminus)

(SEQ ID NO: 7132) 5′-CAAUUUUAAAGUCUUCUGAUGUC^(g)t-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGACUACAG_(U)A-5′Optionally, the mismatched ‘g’ residue of position 24 of the sensestrand is alternatively ‘t’ or ‘c’.LDHA-1287 25/27mer DsiRNA, mismatch position=25 of sense strand (from5′-terminus)

(SEQ ID NO: 7133) 5′-CAAUUUUAAAGUCUUCUGAUGUCa^(a)-3′ (SEQ ID NO: 108)3′-ACGUUAAAAUUUCAGAAGACUACAGU_(A)-5′Optionally, the mismatched ‘a’ residue of position 25 of the sensestrand is alternatively ‘c’ or ‘g’.LDHA-1287 25/27mer DsiRNA, mismatch position=1 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUGAUGUCa^(t)-3′ (SEQ ID NO: 7134)3′-ACGUUAAAAUUUCAGAAGACUACAGU_(U)-5′Optionally, the mismatched ‘U’ residue of position 1 of the antisensestrand is alternatively ‘G’ or ‘C’.LDHA-1287 25/27mer DsiRNA, mismatch position=2 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUGAUGUC^(a)t-3′ (SEQ ID NO: 7135)3′-ACGUUAAAAUUUCAGAAGACUACAG_(C)A-5′Optionally, the mismatched ‘C’ residue of position 2 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=3 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUGAUGU^(C)at-3′ (SEQ ID NO: 7136)3′-ACGUUAAAAUUUCAGAAGACUACA_(U)UA-5′Optionally, the mismatched ‘U’ residue of position 3 of the antisensestrand is alternatively ‘A’ or ‘C’.LDHA-1287 25/27mer DsiRNA, mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUGAUG^(U)Cat-3′ (SEQ ID NO: 7137)3′-ACGUUAAAAUUUCAGAAGACUAC_(C)GUA-5′Optionally, the mismatched ‘C’ residue of position 4 of the antisensestrand is alternatively ‘U’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=5 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUGAU^(G)UCat-3′ (SEQ ID NO: 7138)3′-ACGUUAAAAUUUCAGAAGACUA_(U)AGUA-5′Optionally, the mismatched ‘U’ residue of position 5 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=6 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUGA^(U)GUCat-3 (SEQ ID NO: 7139)3′-ACGUUAAAAUUUCAGAAGACU_(U)CAGUA-5′Optionally, the mismatched ‘U’ residue of position 6 of the antisensestrand is alternatively ‘C’ or ‘G’.LDHA-1287 25/27mer DsiRNA, mismatch position=7 of antisense strand (from5′-terminus)

(SEQ ID NO: 252) 5′-CAAUUUUAAAGUCUUCUG^(A)UGUCat-3 (SEQ ID NO: 7140)3′-ACGUUAAAAUUUCAGAAGAC_(A)ACAGUA-5′Optionally, the mismatched ‘A’ residue of position 7 of the antisensestrand is alternatively ‘C’ or ‘G’.

For the above oligonucleotide strand sequences, it is contemplated thatthe sense strand sequence of one depicted duplex can be combined with anantisense strand of another depicted duplex, thereby forming a distinctduplex—in certain instances, such duplexes contain a mismatched residuewith respect to the lactate dehydrogenase target transcript sequence,while such sense and antisense strand sequences do not present amismatch at this residue with respect to one another (e.g., duplexescomprising SEQ ID NOs: 7127 and 7140; SEQ ID NOs: 7128 and 7139; SEQ IDNOs: 7129 and 7138, etc., are contemplated as exemplary of suchduplexes).

In further exemplary structures, mismatches are introduced within theasymmetric LDHA-370 DsiRNA (newly-introduced mismatch residues areitalicized):

LDHA-370 25/27mer DsiRNA, mismatch position=19 of sense strand (from5′-terminus)

(SEQ ID NO: 7145) 5′-UUGUUGGGGUUGGUGCUG^(A)UGGCat-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGAC_(A)ACCGUA-5′Optionally, the mismatched ‘A’ residue of position 19 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-370 25/27mer DsiRNA, mismatch position=20 of sense strand (from5′-terminus)

(SEQ ID NO: 7146) 5′-UUGUUGGGGUUGGUGCUGU^(A)GGCat-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGACA_(A)CCGUA-5′Optionally, the mismatched ‘A’ residue of position 20 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-370 5/7mer DsiRNA mismatch position=21 of sense strand (from5′-terminus)

(SEQ ID NO: 7147) 5′-UUGUUGGGGUUGGUGCUGUU^(A)GCat-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGACAA_(C)CGUA-5′Optionally, the mismatched ‘A’ residue of position 21 of the sensestrand is alternatively ‘U’ or ‘C’.LDHA-370 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

(SEQ ID NO: 7148) 5′-UUGUUGGGGUUGGUGCUGUUG^(U)Cat-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGACAAC_(C)GUA-5′Optionally, the mismatched ‘U’ residue of position 22 of the sensestrand is alternatively ‘A’ or ‘C’.LDHA-370 25/27mer DsiRNA, mismatch position=23 of sense strand (from5′-terminus)

(SEQ ID NO: 7149) 5′-UUGUUGGGGUUGGUGCUGUUGG^(A)at-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGACAACC_(G)UA-5′Optionally, the mismatched ‘A’ residue of position 23 of the sensestrand is alternatively ‘U’ or ‘G’.LDHA-370 25/27mer DsiRNA, mismatch position=24 of sense strand (from5′-terminus)

(SEQ ID NO: 7150) 5′-UUGUUGGGGUUGGUGCUGUUGGC^(g)t-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGACAACCG_(U)A-5′Optionally, the mismatched ‘g’ residue of position 24 of the sensestrand is alternatively ‘t’ or ‘c’.LDHA-370 25/27mer DsiRNA, mismatch position=25 of sense strand (from5′-terminus)

(SEQ ID NO: 7151) 5′-UUGUUGGGGUUGGUGCUGUUGGCa^(a)-3′ (SEQ ID NO: 84)3′-UCAACAACCCCAACCACGACAACCGU_(A)-5′Optionally, the mismatched ‘a’ residue of position 25 of the sensestrand is alternatively ‘c’ or LDHA-370 25/27mer DsiRNA, mismatchposition=1 of antisense strand (from 5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUGUUGGCa^(t)-3′ (SEQ ID NO: 7152)3′-UCAACAACCCCAACCACGACAACCGU_(U)-5′Optionally, the mismatched ‘U’ residue of position 1 of the antisensestrand is alternatively ‘G’ or ‘C’.LDHA-370 25/27mer DsiRNA, mismatch position=2 of antisense strand (from5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUGUUGGC^(a)t-3′ (SEQ ID NO: 7153)3′-UCAACAACCCCAACCACGACAACCG_(C)A-5′Optionally, the mismatched ‘C’ residue of position 2 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-370 25/27mer DsiRNA, mismatch position=3 of antisense strand (from5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUGUUGG^(C)at-3′ (SEQ ID NO: 7154)3′-UCAACAACCCCAACCACGACAACC_(U)UA-5′Optionally, the mismatched ‘U’ residue of position 3 of the antisensestrand is alternatively ‘A’ or ‘C’.LDHA-370 25/27mer DsiRNA mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUGUUG^(G)Cat-3′ (SEQ ID NO: 7155)3′-UCAACAACCCCAACCACGACAAC_(A)GUA-5′Optionally, the mismatched ‘A’ residue of position 4 of the antisensestrand is alternatively ‘U’ or ‘G’.LDHA-370 25/27mer DsiRNA, mismatch position=5 of antisense strand (from5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUGUU^(G)GCat-3′ (SEQ ID NO: 7156)3′-UCAACAACCCCAACCACGACAA_(U)CGUA-5′Optionally, the mismatched ‘U’ residue of position 5 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-370 25/27mer DsiRNA, mismatch position=6 of antisense strand (from5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUGU^(U)GGCat-3′ (SEQ ID NO: 7157)3′-UCAACAACCCCAACCACGACA_(U)CCGUA-5′Optionally, the mismatched ‘U’ residue of position 6 of antisense strandis alternatively ‘C’ or ‘G’.LDHA-370 25/27mer DsiRNA, mismatch position=7 of antisense strand (from5′-terminus)

(SEQ ID NO: 12) 5′-UUGUUGGGGUUGGUGCUG^(U)UGGCat-3′ (SEQ ID NO: 7158)3′-UCAACAACCCCAACCACGAC_(U)ACCGUA-5′Optionally, the mismatched ‘U’ residue of position 7 of the antisensestrand is alternatively ‘C’ or ‘G’.

As another example, in the below structures, such mismatches areintroduced within the asymmetric LDHA-402 DsiRNA (newly-introducedmismatch residues are italicized):

LDHA-402 25/27mer DsiRNA, mismatch position=19 of sense strand (from5′-terminus)

(SEQ ID NO: 7159) 5′-GCCAUCAGUAUCUUAAUG^(U)AGGAct-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUAC_(U)UCCUGA-5′Optionally, the mismatched ‘U’ residue of position 19 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=20 of sense strand (from5′-terminus)

(SEQ ID NO: 7160) 5′-GCCAUCAGUAUCUUAAUGA^(U)GGAct-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUACU_(U)CCUGA-5′Optionally, the mismatched ‘U’ residue of position 20 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=21 of sense strand (from5′-terminus)

(SEQ ID NO: 7161) 5′-GCCAUCAGUAUCUUAAUGAA^(A)GAct-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUACUU_(C)CUGA-5′Optionally, the mismatched ‘A’ residue of position 21 of the sensestrand is alternatively ‘U’ or ‘C’.LDHA-402 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

(SEQ ID NO: 7162) 5′-GCCAUCAGUAUCUUAAUGAAG^(U)Act-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUACUUC_(C)UGA-5′Optionally, the mismatched ‘U’ residue of position 22 of the sensestrand is alternatively ‘A’ or ‘C’.LDHA-402 25/27mer DsiRNA, mismatch position=23 of sense strand (from5′-terminus)

(SEQ ID NO: 7163) 5′-GCCAUCAGUAUCUUAAUGAAGG^(U)ct-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUACUUCC_(U)GA-5′Optionally, the mismatched ‘U’ residue of position 23 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=24 of sense strand (from5′-terminus)

(SEQ ID NO: 7164) 5′-GCCAUCAGUAUCUUAAUGAAGGA^(t)t-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUACUUCCU_(G)A-5′Optionally, the mismatched ‘t’ residue of position 24 of the sensestrand is alternatively ‘a’ or ‘g’.LDHA-402 25/27mer DsiRNA, mismatch position=25 of sense strand (from5′-terminus)

(SEQ ID NO: 7165) 5′-GCCAUCAGUAUCUUAAUGAAGGAc^(a)-3′ (SEQ ID NO: 90)3′-CACGGUAGUCAUAGAAUUACUUCCUG_(A)-5′Optionally, the mismatched ‘a’ residue of position 25 of the sensestrand is alternatively ‘c’ or ‘g’.LDHA-402 25/27mer DsiRNA, mismatch position=1 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUGAAGGAc^(t)-3′ (SEQ ID NO: 7166)3′-CACGGUAGUCAUAGAAUUACUUCCUG_(U)-5′Optionally, the mismatched ‘U’ residue of position 1 of the antisensestrand is alternatively ‘G’ or ‘C’.LDHA-402 25/27mer DsiRNA, mismatch position=2 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUGAAGGA^(c)t-3′ (SEQ ID NO: 7167)3′-CACGGUAGUCAUAGAAUUACUUCCU_(A)A-5′Optionally, the mismatched ‘A’ residue of position 2 of the antisensestrand is alternatively ‘U’ or ‘C’.LDHA-402 25/27mer DsiRNA, mismatch position=3 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUGAAGG^(A)ct-3′ (SEQ ID NO: 7168)3′-CACGGUAGUCAUAGAAUUACUUCC_(A)GA-5′Optionally, the mismatched ‘A’ residue of position 3 of the antisensestrand is alternatively ‘C’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUGAAG^(G)Act-3′ (SEQ ID NO: 7169)3′-CACGGUAGUCAUAGAAUUACUUC_(A)UGA-5′Optionally, the mismatched ‘A’ residue of position 4 of the antisensestrand is alternatively ‘U’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=5 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUGAA^(G)GAct-3′ (SEQ ID NO: 7170)3′-CACGGUAGUCAUAGAAUUACUU_(U)CUGA-5′Optionally, the mismatched ‘U’ residue of position 5 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=6 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUGA^(A)GGAct-3′ (SEQ ID NO: 7171)3′-CACGGUAGUCAUAGAAUUACU_(A)CCUGA-5′Optionally, the mismatched ‘A’ residue of position 6 of the antisensestrand is alternatively ‘C’ or ‘G’.LDHA-402 25/27mer DsiRNA, mismatch position=7 of antisense strand (from5′-terminus)

(SEQ ID NO: 18) 5′-GCCAUCAGUAUCUUAAUG^(A)AGGAct-3′ (SEQ ID NO: 7172)3′-CACGGUAGUCAUAGAAUUAC_(A)UCCUGA-5′Optionally, the mismatched ‘A’ residue of position 7 of the antisensestrand is alternatively ‘C’ or ‘G’.

As an additional example, in the below structures, such mismatches areintroduced within the asymmetric LDHA-723 DsiRNA (newly-introducedmismatch residues are italicized):

LDHA-723 25/27mer DsiRNA, mismatch position=19 of sense strand (from5′-terminus)

(SEQ ID NO: 7173) 5′-UUGACCUACGUGGCUUGG^(U)AGAUaa-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACC_(U)UCUAUU-5′Optionally, the mismatched ‘U’ residue of position 19 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=20 of sense strand (from5′-terminus)

(SEQ ID NO: 7174) 5′-UUGACCUACGUGGCUUGGA^(U)GAUaa-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACCU_(U)CUAUU-5′Optionally, the mismatched ‘U’ residue of position 20 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=21 of sense strand (from5′-terminus)

(SEQ ID NO: 7175) 5′-UUGACCUACGUGGCUUGGA^(U)GAUaa-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACCUU_(C)UAUU-5′Optionally, the mismatched ‘A’ residue of position 21 of the sensestrand is alternatively ‘U’ or ‘C’.LDHA-723 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

(SEQ ID NO: 7176) 5′-UUGACCUACGUGGCUUGGAAG^(G)Uaa-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACCUUC_(U)AUU-5′Optionally, the mismatched ‘G’ residue of position 22 of the sensestrand is alternatively ‘U’ or ‘C’.LDHA-723 25/27mer DsiRNA, mismatch position=23 of sense strand (from5′-terminus)

(SEQ ID NO: 7177) 5′-UUGACCUACGUGGCUUGGAAGA^(A)aa-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACCUUCU_(A)UU-5′Optionally, the mismatched ‘A’ residue of position 23 of the sensestrand is alternatively ‘C’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=24 of sense strand (from5′-terminus)

(SEQ ID NO: 7178) 5′-UUGACCUACGUGGCUUGGAAGAU^(g)a-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACCUUCUA_(U)U-5′Optionally, the mismatched ‘g’ residue of position 24 of the sensestrand is alternatively ‘t’ or ‘c’.LDHA-723 25/27mer DsiRNA, mismatch position=25 of sense strand (from5′-terminus)

(SEQ ID NO: 7179) 5′-UUGACCUACGUGGCUUGGAAGAUa^(t)-3′ (SEQ ID NO: 99)3′-AGAACUGGAUGCACCGAACCUUCUAU_(U)-5′Optionally, the mismatched ‘t’ residue of position 25 of the antisensestrand is alternatively ‘c’ or ‘g’.LDHA-723 25/27mer DsiRNA, mismatch position=1 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGGAAGAUa^(a)-3′ (SEQ ID NO: 7180)3′-AGAACUGGAUGCACCGAACCUUCUAU_(A)-5′Optionally, the mismatched ‘U’ residue of position 3 of the antisensestrand is alternatively ‘C’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGGAAGAU^(a)a-3′ (SEQ ID NO: 7181)3′-AGAACUGGAUGCACCGAACCUUCUA_(C)U-5′Optionally, the mismatched ‘C’ residue of position 2 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=3 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGGAAGA^(U)aa-3′ (SEQ ID NO: 7182)3′-AGAACUGGAUGCACCGAACCUUCU_(U)UU-5′Optionally, the mismatched ‘U’ residue of position 3 of the antisensestrand is alternatively ‘C’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGGAAG^(A)Uaa-3′ (SEQ ID NO: 7183)3′-AGAACUGGAUGCACCGAACCUUC_(C)AUU-5′Optionally, the mismatched ‘C’ residue of position 4 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=5 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGGAA^(G)AUaa-3′ (SEQ ID NO: 7184)3′-AGAACUGGAUGCACCGAACCUU_(U)UAUU-5′Optionally, the mismatched ‘U’ residue of position 5 of the antisensestrand is alternatively ‘A’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=6 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGGA^(A)GAUaa-3′ (SEQ ID NO: 7185)3′-AGAACUGGAUGCACCGAACCU_(A)CUAUU-5′Optionally, the mismatched ‘A’ residue of position 6 of the antisensestrand is alternatively ‘C’ or ‘G’.LDHA-723 25/27mer DsiRNA, mismatch position=7 of antisense strand (from5′-terminus)

(SEQ ID NO: 27) 5′-UUGACCUACGUGGCUUGG^(A)AGAUaa-3′ (SEQ ID NO: 7186)3′-AGAACUGGAUGCACCGAACC_(A)UCUAUU-5′Optionally, the mismatched ‘A’ residue of position 7 of the antisensestrand is alternatively ‘C’ or ‘G’.

As noted above, introduction of mismatches can be performed upon any ofthe DsiRNAs described herein.

The mismatches of such DsiRNA structures can be combined to produce aDsiRNA possessing, e.g., two, three or even four mismatches within the3′-terminal four to seven nucleotides of the sense strand/5′-terminalfour to seven nucleotides of the antisense strand.

Indeed, in view of the flexibility of sequences which can beincorporated into DsiRNAs at the 3′-terminal residues of the sensestrand/5′-terminal residues of the antisense strand, in certainembodiments, the sequence requirements of an asymmetric DsiRNA of theinstant invention can be represented as the following (minimalist)structure (shown for an exemplary lactate dehydrogenase-1365 DsiRNAsequence):

(SEQ ID NO: 7141) 5′-GUCCUUUUUAUCUGAUCUXXXXXX[X]_(n)-3′ (SEQ ID NO:7142) 3′-AACAGGAAAAAUAGACUAGAXXXXXX[X]_(n)-5′where n=1 to 5, 1 to 10, 1 to 20, 1 to 30, 1 to 50, or 1 to 80 or more.lactate dehydrogenase-1365 mRNA Target:

(SEQ ID NO: 7143) 5′-UUGUCCUUUUUAUCUGAUCUXXXXXXX-3′.

The lactate dehydrogenase target site may also be a site which istargeted by one or more of several oligonucleotides whose complementarytarget sites overlap with a stated target site. For example, for anexemplary lactate dehydrogenase-1365 DsiRNA, it is noted that certainDsiRNAs targeting overlapping and only slightly offset lactatedehydrogenase sequences could exhibit activity levels similar to that oflactate dehydrogenase-1635 (e.g., lactate dehydrogenase-1359 to 1372 ofTable 2 above). Thus, in certain embodiments, a designated targetsequence region might be effectively targeted by a series of DsiRNAspossessing largely overlapping sequences. (E.g., if considering DsiRNAsof the lactate dehydrogenase-1359 to lactate dehydrogenase-1372 targetsite(s), a more encompassing lactate dehydrogenase transcript targetsequence might be recited as, e.g.

(SEQ ID NO: 7144) 5′-UGCAUGUUGUCCUUUUUAUCUGAUCUGUGAUUAAAGCAGU-3′,7144), wherein any given DsiRNA (e.g., a DsiRNA selected from lactatedehydrogenase-1359 to lactate dehydrogenase-1372) only targets asub-sequence within such a sequence region, yet the entire sequence canbe considered a viable target for such a series of DsiRNAs).

Additionally and/or alternatively, mismatches within the 3′-terminalseven nucleotides of the sense strand/5′-terminal seven nucleotides ofthe antisense strand can be combined with mismatches positioned at othermismatch-tolerant positions, as described above.

In view of the present identification of the above-described Dicersubstrate agents (DsiRNAs) as inhibitors of lactate dehydrogenase levelsvia targeting of specific lactate dehydrogenase sequences, it is alsorecognized that dsRNAs having structures similar to those describedherein can also be synthesized which target other sequences within thelactate dehydrogenase sequence of NM_005566.3, or within variantsthereof (e.g., target sequences possessing 80% identity, 90% identity,95% identity, 96% identity, 97% identity, 98% identity, 99% or moreidentity to a sequence of NM_005566.3).

Anti-Lactate Dehydrogenase DsiRNA Design/Synthesis

It has been found empirically that longer dsRNA species of from 25 to 35nucleotides (DsiRNAs) and especially from 25 to 30 nucleotides giveunexpectedly effective results in terms of potency and duration ofaction, as compared to 19-23mer siRNA agents. Without wishing to bebound by the underlying theory of the dsRNA processing mechanism, it isthought that the longer dsRNA species serve as a substrate for the Dicerenzyme in the cytoplasm of a cell. In addition to cleaving the dsRNA ofthe invention into shorter segments, Dicer is thought to facilitate theincorporation of a single-stranded cleavage product derived from thecleaved dsRNA into the RISC complex that is responsible for thedestruction of the cytoplasmic RNA (e.g., lactate dehydrogenase RNA) ofor derived from the target gene, lactate dehydrogenase (or other geneassociated with a lactate dehydrogenase-associated disease or disorder).Prior studies (Rossi et al., U.S. Patent Application No. 2007/0265220)have shown that the cleavability of a dsRNA species (specifically, aDsiRNA agent) by Dicer corresponds with increased potency and durationof action of the dsRNA species.

Certain preferred anti-lactate dehydrogenase DsiRNA agents were selectedfrom a pre-screened population. Design of DsiRNAs can optionally involveuse of predictive scoring algorithms that perform in silico assessmentsof the projected activity/efficacy of a number of possible DsiRNA agentsspanning a region of sequence. Information regarding the design of suchscoring algorithms can be found, e.g., in Gong et al. (BMCBioinformatics 2006, 7:516), though a more recent “v4.3” algorithmrepresents a theoretically improved algorithm relative to siRNA scoringalgorithms previously available in the art. (E.g., “v3” and “v4” scoringalgorithms are machine learning algorithms that are not reliant upon anybiases in human sequence. In addition, the “v3” and “v4” algorithmsderive from data sets that are many-fold larger than that from which anolder “v2” algorithm such as that described in Gong et al. derives.)

The first and second oligonucleotides of the DsiRNA agents of theinstant invention are not required to be completely complementary. Infact, in one embodiment, the 3′-terminus of the sense strand containsone or more mismatches. In one aspect, two mismatches are incorporatedat the 3′ terminus of the sense strand. In another embodiment, theDsiRNA of the invention is a double stranded RNA molecule containing twoRNA oligonucleotides each of which is 27 nucleotides in length and, whenannealed to each other, have blunt ends and a two nucleotide mismatch onthe 3′-terminus of the sense strand (the 5′-terminus of the antisensestrand). The use of mismatches or decreased thermodynamic stability(specifically at the 3′-sense/5′-antisense position) has been proposedto facilitate or favor entry of the antisense strand into RISC (Schwarzet al., 2003, Cell 115: 199-208; Khvorova et al., 2003, Cell 115:209-216), presumably by affecting some rate-limiting unwinding stepsthat occur with entry of the siRNA into RISC. Thus, terminal basecomposition has been included in design algorithms for selecting active21 mer siRNA duplexes (Ui-Tei et al., 2004, Nucleic Acids Res 32:936-948; Reynolds et al., 2004, Nat Biotechnol 22: 326-330). With Dicercleavage of the dsRNA of this embodiment, the small end-terminalsequence which contains the mismatches will either be left unpaired withthe antisense strand (become part of a 3′-overhang) or be cleavedentirely off the final 21-mer siRNA. These “mismatches”, therefore, donot persist as mismatches in the final RNA component of RISC. Thefinding that base mismatches or destabilization of segments at the3′-end of the sense strand of Dicer substrate improved the potency ofsynthetic duplexes in RNAi, presumably by facilitating processing byDicer, was a surprising finding of past works describing the design anduse of 25-30mer dsRNAs (also termed “DsiRNAs” herein; Rossi et al., U.S.Patent Application Nos. 2005/0277610, 2005/0244858 and 2007/0265220).

Modification of Anti-Lactate Dehydrogenase dsRNAs

One major factor that inhibits the effect of double stranded RNAs(“dsRNAs”) is the degradation of dsRNAs (e.g., siRNAs and DsiRNAs) bynucleases. A 3′-exonuclease is the primary nuclease activity present inserum and modification of the 3′-ends of antisense DNA oligonucleotidesis crucial to prevent degradation (Eder et al., 1991, Antisense Res Dev,1: 141-151). An RNase-T family nuclease has been identified called ERI-1which has 3′ to 5′ exonuclease activity that is involved in regulationand degradation of siRNAs (Kennedy et al., 2004, Nature 427: 645-649;Hong et al., 2005, Biochem J, 390: 675-679). This gene is also known asThex1 (NM_02067) in mice or THEX1 (NM_153332) in humans and is involvedin degradation of histone mRNA; it also mediates degradation of3′-overhangs in siRNAs, but does not degrade duplex RNA (Yang et al.,2006, J Biol Chem, 281: 30447-30454). It is therefore reasonable toexpect that 3′-end-stabilization of dsRNAs, including the DsiRNAs of theinstant invention, will improve stability.

XRN1 (NM_019001) is a 5′ to 3′ exonuclease that resides in P-bodies andhas been implicated in degradation of mRNA targeted by miRNA (Rehwinkelet al., 2005, RNA 11: 1640-1647) and may also be responsible forcompleting degradation initiated by internal cleavage as directed by asiRNA. XRN2 (NM_012255) is a distinct 5′ to 3′ exonuclease that isinvolved in nuclear RNA processing.

RNase A is a major endonuclease activity in mammals that degrades RNAs.It is specific for ssRNA and cleaves at the 3′-end of pyrimidine bases.SiRNA degradation products consistent with RNase A cleavage can bedetected by mass spectrometry after incubation in serum (Turner et al.,2007, Mol Biosyst 3: 43-50). The 3′-overhangs enhance the susceptibilityof siRNAs to RNase degradation. Depletion of RNase A from serum reducesdegradation of siRNAs; this degradation does show some sequencepreference and is worse for sequences having poly A/U sequence on theends (Haupenthal et al., 2006 Biochem Pharmacol 71: 702-710). Thissuggests the possibility that lower stability regions of the duplex may“breathe” and offer transient single-stranded species available fordegradation by RNase A. RNase A inhibitors can be added to serum andimprove siRNA longevity and potency (Haupenthal et al., 2007, Int J.Cancer 121: 206-210).

In 21 mers, phosphorothioate or boranophosphate modifications directlystabilize the internucleoside phosphate linkage. Boranophosphatemodified RNAs are highly nuclease resistant, potent as silencing agents,and are relatively non-toxic. Boranophosphate modified RNAs cannot bemanufactured using standard chemical synthesis methods and instead aremade by in vitro transcription (IVT) (Hall et al., 2004, Nucleic AcidsRes 32: 5991-6000; Hall et al., 2006, Nucleic Acids Res 34: 2773-2781).Phosphorothioate (PS) modifications can be easily placed in the RNAduplex at any desired position and can be made using standard chemicalsynthesis methods. The PS modification shows dose-dependent toxicity, somost investigators have recommended limited incorporation in siRNAs,favoring the 3′-ends where protection from nucleases is most important(Harborth et al., 2003, Antisense Nucleic Acid Drug Dev 13: 83-105; Chiuand Rana, 2003, Mol Cell 10: 549-561; Braasch et al., 2003, Biochemistry42: 7967-7975; Amarzguioui et al., 2003, Nucleic Acids Research 31:589-595). More extensive PS modification can be compatible with potentRNAi activity; however, use of sugar modifications (such as 2′-O-methylRNA) may be superior (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927).

A variety of substitutions can be placed at the 2′-position of theribose which generally increases duplex stability (Tm) and can greatlyimprove nuclease resistance. 2′-O-methyl RNA is a naturally occurringmodification found in mammalian ribosomal RNAs and transfer RNAs.2′-O-methyl modification in siRNAs is known, but the precise position ofmodified bases within the duplex is important to retain potency andcomplete substitution of 2′-O-methyl RNA for RNA will inactivate thesiRNA. For example, a pattern that employs alternating 2′-O-methyl basescan have potency equivalent to unmodified RNA and is quite stable inserum (Choung et al., 2006, Biochem Biophys Res Commun 342: 919-927;Czauderna et al., 2003, Nucleic Acids Research 31: 2705-2716).

The 2′-fluoro (2′-F) modification is also compatible with dsRNA (e.g.,siRNA and DsiRNA) function; it is most commonly placed at pyrimidinesites (due to reagent cost and availability) and can be combined with2′-O-methyl modification at purine positions; 2′-F purines are availableand can also be used. Heavily modified duplexes of this kind can bepotent triggers of RNAi in vitro (Allerson et al., 2005, J Med Chem 48:901-904; Prakash et al., 2005, J Med Chem 48: 4247-4253; Kraynack andBaker, 2006, RNA 12: 163-176) and can improve performance and extendduration of action when used in vivo (Morrissey et al., 2005, Hepatology41: 1349-1356; Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007). Ahighly potent, nuclease stable, blunt 19mer duplex containingalternative 2′-F and 2′-O-Me bases is taught by Allerson. In thisdesign, alternating 2′-O-Me residues are positioned in an identicalpattern to that employed by Czauderna, however the remaining RNAresidues are converted to 2′-F modified bases. A highly potent, nucleaseresistant siRNA employed by Morrissey employed a highly potent, nucleaseresistant siRNA in vivo. In addition to 2′-O-Me RNA and 2′-F RNA, thisduplex includes DNA, RNA, inverted abasic residues, and a 3′-terminal PSinternucleoside linkage. While extensive modification has certainbenefits, more limited modification of the duplex can also improve invivo performance and is both simpler and less costly to manufacture.Soutschek et al. (2004, Nature 432: 173-178) employed a duplex in vivoand was mostly RNA with two 2′-O-Me RNA bases and limited 3′-terminal PSinternucleoside linkages.

Locked nucleic acids (LNAs) are a different class of 2′-modificationthat can be used to stabilize dsRNA (e.g., siRNA and DsiRNA). Patternsof LNA incorporation that retain potency are more restricted than2′-O-methyl or 2′-F bases, so limited modification is preferred (Braaschet al., 2003, Biochemistry 42: 7967-7975; Grunweller et al., 2003,Nucleic Acids Res 31: 3185-3193; Elmen et al., 2005, Nucleic Acids Res33: 439-447). Even with limited incorporation, the use of LNAmodifications can improve dsRNA performance in vivo and may also alteror improve off target effect profiles (Mook et al., 2007, Mol CancerTher 6: 833-843).

Synthetic nucleic acids introduced into cells or live animals can berecognized as “foreign” and trigger an immune response. Immunestimulation constitutes a major class of off-target effects which candramatically change experimental results and even lead to cell death.The innate immune system includes a collection of receptor moleculesthat specifically interact with DNA and RNA that mediate theseresponses, some of which are located in the cytoplasm and some of whichreside in endosomes (Marques and Williams, 2005, Nat Biotechnol 23:1399-1405; Schlee et al., 2006, Mol Ther 14: 463-470). Delivery ofsiRNAs by cationic lipids or liposomes exposes the siRNA to bothcytoplasmic and endosomal compartments, maximizing the risk fortriggering a type 1 interferon (IFN) response both in vitro and in vivo(Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007; Sioud andSorensen, 2003, Biochem Biophys Res Commun 312: 1220-1225; Sioud, 2005,J Mol Biol 348: 1079-1090; Ma et al., 2005, Biochem Biophys Res Commun330: 755-759). RNAs transcribed within the cell are less immunogenic(Robbins et al., 2006, Nat Biotechnol 24: 566-571) and synthetic RNAsthat are immunogenic when delivered using lipid-based methods can evadeimmune stimulation when introduced unto cells by mechanical means, evenin vivo (Heidel et al., 2004, Nat Biotechnol 22: 1579-1582). However,lipid based delivery methods are convenient, effective, and widely used.Some general strategy to prevent immune responses is needed, especiallyfor in vivo application where all cell types are present and the risk ofgenerating an immune response is highest. Use of chemically modifiedRNAs may solve most or even all of these problems.

In certain embodiments, modifications can be included in theanti-lactate dehydrogenase dsRNA agents of the present invention so longas the modification does not prevent the dsRNA agent from possessinglactate dehydrogenase inhibitory activity. In one embodiment, one ormore modifications are made that enhance Dicer processing of the DsiRNAagent (an assay for determining Dicer processing of a DsiRNA isdescribed elsewhere herein). In a second embodiment, one or moremodifications are made that result in more effective lactatedehydrogenase inhibition (as described herein, lactate dehydrogenaseinhibition/lactate dehydrogenase inhibitory activity of a dsRNA can beassayed via art-recognized methods for determining RNA levels, or fordetermining lactate dehydrogenase polypeptide levels, should such levelsbe assessed in lieu of or in addition to assessment of, e.g., lactatedehydrogenase mRNA levels). In a third embodiment, one or moremodifications are made that support greater lactate dehydrogenaseinhibitory activity (means of determining lactate dehydrogenaseinhibitory activity are described supra). In a fourth embodiment, one ormore modifications are made that result in greater potency of lactatedehydrogenase inhibitory activity per each dsRNA agent molecule to bedelivered to the cell (potency of lactate dehydrogenase inhibitoryactivity is described supra). Modifications can be incorporated in the3′-terminal region, the 5′-terminal region, in both the 3′-terminal and5′-terminal region or in some instances in various positions within thesequence. With the restrictions noted above in mind, numbers andcombinations of modifications can be incorporated into the dsRNA agent.Where multiple modifications are present, they may be the same ordifferent. Modifications to bases, sugar moieties, the phosphatebackbone, and their combinations are contemplated. Either 5′-terminuscan be phosphorylated.

Examples of modifications contemplated for the phosphate backboneinclude phosphonates, including methylphosphonate, phosphorothioate, andphosphotriester modifications such as alkylphosphotriesters, and thelike. Examples of modifications contemplated for the sugar moietyinclude 2′-alkyl pyrimidine, such as 2′-O-methyl, 2′-fluoro, amino, anddeoxy modifications and the like (see, e.g., Amarzguioui et al., 2003,Nucleic Acids Research 31: 589-595). Examples of modificationscontemplated for the base groups include abasic sugars, 2-O-alkylmodified pyrimidines, 4-thiouracil, 5-bromouracil, 5-iodouracil, and5-(3-aminoallyl)-uracil and the like. Locked nucleic acids, or LNA's,could also be incorporated. Many other modifications are known and canbe used so long as the above criteria are satisfied. Examples ofmodifications are also disclosed in U.S. Pat. Nos. 5,684,143, 5,858,988and 6,291,438 and in U.S. published patent application No. 2004/0203145A1. Other modifications are disclosed in Herdewijn (2000, AntisenseNucleic Acid Drug Dev 10: 297-310), Eckstein (2000, Antisense NucleicAcid Drug Dev 10: 117-21), Rusckowski et al. (2000, Antisense NucleicAcid Drug Dev 10: 333-345), Stein et al. (2001, Antisense Nucleic AcidDrug Dev 11: 317-25); Vorobjev et al. (2001, Antisense Nucleic Acid DrugDev 11: 77-85).

One or more modifications contemplated can be incorporated into eitherstrand. The placement of the modifications in the dsRNA agent cangreatly affect the characteristics of the dsRNA agent, includingconferring greater potency and stability, reducing toxicity, enhanceDicer processing, and minimizing an immune response. In one embodiment,the antisense strand or the sense strand or both strands have one ormore 2′-O-methyl modified nucleotides. In another embodiment, theantisense strand contains 2′-O-methyl modified nucleotides. In anotherembodiment, the antisense stand contains a 3′ overhang that is comprisedof 2′-O-methyl modified nucleotides. The antisense strand could alsoinclude additional 2′-O-methyl modified nucleotides.

In certain embodiments, the anti-lactate dehydrogenase DsiRNA agent ofthe invention has several properties which enhance its processing byDicer. According to such embodiments, the DsiRNA agent has a lengthsufficient such that it is processed by Dicer to produce an siRNA and atleast one of the following properties: (i) the DsiRNA agent isasymmetric, e.g., has a 3′ overhang on the sense strand and (ii) theDsiRNA agent has a modified 3′ end on the antisense strand to directorientation of Dicer binding and processing of the dsRNA to an activesiRNA. According to these embodiments, the longest strand in the DsiRNAagent comprises 25-30 nucleotides. In one embodiment, the sense strandcomprises 25-30 nucleotides and the antisense strand comprises 25-28nucleotides. Thus, the resulting dsRNA has an overhang on the 3′ end ofthe sense strand. The overhang is 1-4 nucleotides, such as 2nucleotides. The antisense strand may also have a 5′ phosphate.

In certain embodiments, the sense strand of a DsiRNA agent is modifiedfor Dicer processing by suitable modifiers located at the 3′ end of thesense strand, i.e., the DsiRNA agent is designed to direct orientationof Dicer binding and processing. Suitable modifiers include nucleotidessuch as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotidesand the like and sterically hindered molecules, such as fluorescentmolecules and the like. Acyclonucleotides substitute a2-hydroxyethoxymethyl group for the 2′-deoxyribofuranosyl sugar normallypresent in dNMPs. Other nucleotide modifiers could include3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the sense strand.When sterically hindered molecules are utilized, they are attached tothe ribonucleotide at the 3′ end of the antisense strand. Thus, thelength of the strand does not change with the incorporation of themodifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the sense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of theantisense strand and the 3′ end of the sense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the antisensestrand. This is an asymmetric composition with DNA on the blunt end andRNA bases on the overhanging end.

In certain other embodiments, the antisense strand of a DsiRNA agent ismodified for Dicer processing by suitable modifiers located at the 3′end of the antisense strand, i.e., the DsiRNA agent is designed todirect orientation of Dicer binding and processing. Suitable modifiersinclude nucleotides such as deoxyribonucleotides,dideoxyribonucleotides, acyclonucleotides and the like and stericallyhindered molecules, such as fluorescent molecules and the like.Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for the2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotidemodifiers could include 3′-deoxyadenosine (cordycepin),3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the antisensestrand. When sterically hindered molecules are utilized, they areattached to the ribonucleotide at the 3′ end of the antisense strand.Thus, the length of the strand does not change with the incorporation ofthe modifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the antisense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of thesense strand and the 3′ end of the antisense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the sensestrand. This is also an asymmetric composition with DNA on the blunt endand RNA bases on the overhanging end.

The sense and antisense strands anneal under biological conditions, suchas the conditions found in the cytoplasm of a cell. In addition, aregion of one of the sequences, particularly of the antisense strand, ofthe dsRNA has a sequence length of at least 19 nucleotides, whereinthese nucleotides are adjacent to the 3′ end of antisense strand and aresufficiently complementary to a nucleotide sequence of the targetlactate dehydrogenase RNA.

Additionally, the DsiRNA agent structure can be optimized to ensure thatthe oligonucleotide segment generated from Dicer's cleavage will be theportion of the oligonucleotide that is most effective in inhibiting geneexpression. For example, in one embodiment of the invention, a 27-bpoligonucleotide of the DsiRNA agent structure is synthesized wherein theanticipated 21 to 22-bp segment that will inhibit gene expression islocated on the 3′-end of the antisense strand. The remaining baseslocated on the 5′-end of the antisense strand will be cleaved by Dicerand will be discarded. This cleaved portion can be homologous (i.e.,based on the sequence of the target sequence) or non-homologous andadded to extend the nucleic acid strand.

US 2007/0265220 discloses that 27mer DsiRNAs showed improved stabilityin serum over comparable 21 mer siRNA compositions, even absent chemicalmodification. Modifications of DsiRNA agents, such as inclusion of2′-O-methyl RNA in the antisense strand, in patterns such as detailedabove, when coupled with addition of a 5′ Phosphate, can improvestability of DsiRNA agents. Addition of 5′-phosphate to all strands insynthetic RNA duplexes may be an inexpensive and physiological method toconfer some limited degree of nuclease stability.

The chemical modification patterns of the dsRNA agents of the instantinvention are designed to enhance the efficacy of such agents.Accordingly, such modifications are designed to avoid reducing potencyof dsRNA agents; to avoid interfering with Dicer processing of DsiRNAagents; to improve stability in biological fluids (reduce nucleasesensitivity) of dsRNA agents; or to block or evade detection by theinnate immune system. Such modifications are also designed to avoidbeing toxic and to avoid increasing the cost or impact the ease ofmanufacturing the instant dsRNA agents of the invention.

In certain embodiments of the present invention, an anti-lactatedehydrogenase DsiRNA agent has one or more of the following properties:(i) the DsiRNA agent is asymmetric, e.g., has a 3′ overhang on theantisense strand and (ii) the DsiRNA agent has a modified 3′ end on thesense strand to direct orientation of Dicer binding and processing ofthe dsRNA to an active siRNA. According to this embodiment, the longeststrand in the dsRNA comprises 25-35 nucleotides (e.g., 25, 26, 27, 28,29, 30, 31, 32, 33, 34 or 35 nucleotides). In certain such embodiments,the DsiRNA agent is asymmetric such that the sense strand comprises25-34 nucleotides and the 3′ end of the sense strand forms a blunt endwith the 5′ end of the antisense strand while the antisense strandcomprises 26-35 nucleotides and forms an overhang on the 3′ end of theantisense strand. In one embodiment, the DsiRNA agent is asymmetric suchthat the sense strand comprises 25-28 nucleotides and the antisensestrand comprises 25-30 nucleotides. Thus, the resulting dsRNA has anoverhang on the 3′ end of the antisense strand. The overhang is 1-4nucleotides, for example 2 nucleotides. The sense strand may also have a5′ phosphate.

The DsiRNA agent can also have one or more of the following additionalproperties: (a) the antisense strand has a right shift from the typical21mer (e.g., the DsiRNA comprises a length of antisense strandnucleotides that extends to the 5′ of a projected Dicer cleavage sitewithin the DsiRNA, with such antisense strand nucleotides base pairedwith corresponding nucleotides of the sense strand extending 3′ of aprojected Dicer cleavage site in the sense strand), (b) the strands maynot be completely complementary, i.e., the strands may contain simplemismatched base pairs (in certain embodiments, the DsiRNAs of theinvention possess 1, 2, 3, 4 or even 5 or more mismatched base pairs,provided that lactate dehydrogenase inhibitory activity of the DsiRNApossessing mismatched base pairs is retained at sufficient levels (e.g.,retains at least 50% lactate dehydrogenase inhibitory activity or more,at least 60% lactate dehydrogenase inhibitory activity or more, at least70% lactate dehydrogenase inhibitory activity or more, at least 80%lactate dehydrogenase inhibitory activity or more, at least 90% lactatedehydrogenase inhibitory activity or more or at least 95% lactatedehydrogenase inhibitory activity or more as compared to a correspondingDsiRNA not possessing mismatched base pairs. In certain embodiments,mismatched base pairs exist between the antisense and sense strands of aDsiRNA. In some embodiments, mismatched base pairs exist (or arepredicted to exist) between the antisense strand and the target RNA. Incertain embodiments, the presence of a mismatched base pair(s) betweenan antisense strand residue and a corresponding residue within thetarget RNA that is located 3′ in the target RNA sequence of a projectedAgo2 cleavage site retains and may even enhance lactate dehydrogenaseinhibitory activity of a DsiRNA of the invention) and (c) basemodifications such as locked nucleic acid(s) may be included in the 5′end of the sense strand. A “typical” 21 mer siRNA is designed usingconventional techniques. In one technique, a variety of sites arecommonly tested in parallel or pools containing several distinct siRNAduplexes specific to the same target with the hope that one of thereagents will be effective (Ji et al., 2003, FEBS Lett 552: 247-252).Other techniques use design rules and algorithms to increase thelikelihood of obtaining active RNAi effector molecules (Schwarz et al.,2003, Cell 115: 199-208; Khvorova et al., 2003, Cell 115: 209-216;Ui-Tei et al., 2004, Nucleic Acids Res 32: 936-948; Reynolds et al.,2004, Nat Biotechnol 22: 326-330; Krol et al., 2004, J Biol Chem 279:42230-42239; Yuan et al., 2004, Nucl Acids Res 32(Webserverissue):W130-134; Boese et al., 2005, Methods Enzymol 392: 73-96). Highthroughput selection of siRNA has also been developed (U.S. publishedpatent application No. 2005/0042641 A1). Potential target sites can alsobe analyzed by secondary structure predictions (Heale et al., 2005,Nucleic Acids Res 33(3): e30). This 21mer is then used to design a rightshift to include 3-9 additional nucleotides on the 5′ end of the 21mer.The sequence of these additional nucleotides is not restricted. In oneembodiment, the added ribonucleotides are based on the sequence of thetarget gene. Even in this embodiment, full complementarity between thetarget sequence and the antisense siRNA is not required.

The first and second oligonucleotides of a DsiRNA agent of the instantinvention are not required to be completely complementary. They onlyneed to be sufficiently complementary to anneal under biologicalconditions and to provide a substrate for Dicer that produces a siRNAsufficiently complementary to the target sequence. Locked nucleic acids,or LNA's, are well known to a skilled artisan (Elmen et al., 2005,Nucleic Acids Res 33: 439-447; Kurreck et al., 2002, Nucleic Acids Res30: 1911-1918; Crinelli et al., 2002, Nucleic Acids Res 30: 2435-2443;Braasch and Corey, 2001, Chem Biol 8: 1-7; Bondensgaard et al., 2000,Chemistry 6: 2687-2695; Wahlestedt et al., 2000, Proc Natl Acad Sci USA97: 5633-5638). In one embodiment, an LNA is incorporated at the 5′terminus of the sense strand. In another embodiment, an LNA isincorporated at the 5′ terminus of the sense strand in duplexes designedto include a 3′ overhang on the antisense strand.

In certain embodiments, the DsiRNA agent of the instant invention has anasymmetric structure, with the sense strand having a 25-base pairlength, and the antisense strand having a 27-base pair length with a 2base 3′-overhang. In other embodiments, this DsiRNA agent having anasymmetric structure further contains 2 deoxynucleotides at the 3′ endof the sense strand in place of two of the ribonucleotides.

Certain DsiRNA agent compositions containing two separateoligonucleotides can be linked by a third structure. The third structurewill not block Dicer activity on the DsiRNA agent and will not interferewith the directed destruction of the RNA transcribed from the targetgene. In one embodiment, the third structure may be a chemical linkinggroup. Many suitable chemical linking groups are known in the art andcan be used. Alternatively, the third structure may be anoligonucleotide that links the two oligonucleotides of the DsiRNA agentin a manner such that a hairpin structure is produced upon annealing ofthe two oligonucleotides making up the dsRNA composition. The hairpinstructure will not block Dicer activity on the DsiRNA agent and will notinterfere with the directed destruction of the lactate dehydrogenaseRNA.

In Vitro Assay to Assess dsRNA Lactate Dehydrogenase Inhibitory Activity

An in vitro assay that recapitulates RNAi in a cell-free system can beused to evaluate dsRNA constructs targeting lactate dehydrogenase RNAsequence(s), and thus to assess lactate dehydrogenase-specific geneinhibitory activity (also referred to herein as lactate dehydrogenaseinhibitory activity) of a dsRNA. The assay comprises the systemdescribed by Tuschl et al., 1999, Genes and Development, 13, 3191-3197and Zamore et al., 2000, Cell, 101, 25-33 adapted for use with dsRNA(e.g., DsiRNA) agents directed against lactate dehydrogenase RNA. ADrosophila extract derived from syncytial blastoderm is used toreconstitute RNAi activity in vitro. Target RNA is generated via invitro transcription from a selected lactate dehydrogenase expressingplasmid using T7 RNA polymerase or via chemical synthesis. Sense andantisense dsRNA strands (for example, 20 uM each) are annealed byincubation in buffer (such as 100 mM potassium acetate, 30 mM HEPES-KOH,pH 7.4, 2 mM magnesium acetate) for 1 minute at 90° C. followed by 1hour at 37° C., then diluted in lysis buffer (for example 100 mMpotassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesium acetate).Annealing can be monitored by gel electrophoresis on an agarose gel inTBE buffer and stained with ethidium bromide. The Drosophila lysate isprepared using zero to two-hour-old embryos from Oregon R fliescollected on yeasted molasses agar that are dechorionated and lysed. Thelysate is centrifuged and the supernatant isolated. The assay comprisesa reaction mixture containing 50% lysate [vol/vol], RNA (10-50 pM finalconcentration), and 10% [vol/vol] lysis buffer containing dsRNA (10 nMfinal concentration). The reaction mixture also contains 10 mM creatinephosphate, 10 ug/ml creatine phosphokinase, 100 um GTP, 100 uM UTP, 100uM CTP, 500 uM ATP, 5 mM DTI, 0.1 U/uL RNasin (Promega), and 100 uM ofeach amino acid. The final concentration of potassium acetate isadjusted to 100 mM. The reactions are pre-assembled on ice andpreincubated at 25° C. for 10 minutes before adding RNA, then incubatedat 25° C. for an additional 60 minutes. Reactions are quenched with 4volumes of 1.25×Passive Lysis Buffer (Promega). Target RNA cleavage isassayed by RT-PCR analysis or other methods known in the art and arecompared to control reactions in which dsRNA is omitted from thereaction.

Alternately, internally-labeled target RNA for the assay is prepared byin vitro transcription in the presence of [α-³²P] CTP, passed over a G50Sephadex column by spin chromatography and used as target RNA withoutfurther purification. Optionally, target RNA is 5′-³²P-end labeled usingT4 polynucleotide kinase enzyme. Assays are performed as described aboveand target RNA and the specific RNA cleavage products generated by RNAiare visualized on an autoradiograph of a gel. The percentage of cleavageis determined by PHOSPHOR IMAGER® (autoradiography) quantitation ofbands representing intact control RNA or RNA from control reactionswithout dsRNA and the cleavage products generated by the assay.

In one embodiment, this assay is used to determine target sites in thelactate dehydrogenase RNA target for dsRNA mediated RNAi cleavage,wherein a plurality of dsRNA constructs are screened for RNAi mediatedcleavage of the lactate dehydrogenase RNA target, for example, byanalyzing the assay reaction by electrophoresis of labeled target RNA,or by northern blotting, as well as by other methodology well known inthe art.

In certain embodiments, a dsRNA of the invention is deemed to possesslactate dehydrogenase inhibitory activity if, e.g., a 50% reduction inlactate dehydrogenase RNA levels is observed in a system, cell, tissueor organism, relative to a suitable control. Additional metes and boundsfor determination of lactate dehydrogenase inhibitory activity of adsRNA of the invention are described supra.

Conjugation and Delivery of Anti-Lactate Dehydrogenase dsRNA Agents

In certain embodiments the present invention relates to a method fortreating a subject having oxalate accumulation, PH1 and/or other lactatedehydrogenase-associated disease or disorder, or is at risk ofdeveloping oxalate accumulation, PH1 and/or other lactatedehydrogenase-associated disease or disorder. In such embodiments, thedsRNA can act as novel therapeutic agents for controlling the oxalateaccumulation, PH1 and/or other lactate dehydrogenase-associated diseaseor disorder. The method comprises administering a pharmaceuticalcomposition of the invention to the patient (e.g., human), such that theexpression, level and/or activity of a lactate dehydrogenase RNA isreduced. The expression, level and/or activity of a polypeptide encodedby a lactate dehydrogenase RNA might also be reduced by a dsRNA of theinstant invention, even where said dsRNA is directed against anon-coding region of the lactate dehydrogenase transcript (e.g., atargeted 5′ UTR or 3′ UTR sequence). Because of their high specificity,the dsRNAs of the present invention can specifically target lactatedehydrogenase sequences of cells and tissues, optionally in anallele-specific manner where polymorphic alleles exist within anindividual and/or population.

In the treatment of oxalate accumulation, PH1 and/or other lactatedehydrogenase-associated disease or disorder, the dsRNA can be broughtinto contact with the cells or tissue of a subject, e.g., the cells ortissue of a subject targeted for reduction of lactate dehydrogenaselevels. For a disease such as PH1 or other disease or disorder ofoxalate accumulation treatable or preventable via administration of ananti-LDHA agent (e.g., a dsRNA of the invention), targeted inhibition ofLDHA preferentially delivered to the liver can be performed via use ofdsRNA therapeutics such as those disclosed herein and deliverymodalities for dsRNA known in the art (e.g., lipid nanoparticles andother moieties that preferentially deliver dsRNA to the liver). Forexample, dsRNA substantially identical to all or part of a lactatedehydrogenase RNA sequence, may be brought into contact with orintroduced into such a cell, either in vivo or in vitro. Similarly,dsRNA substantially identical to all or part of a lactate dehydrogenaseRNA sequence may administered directly to a subject having or at risk ofdeveloping a disease or disorder that could be prevented or treated viaadministration of an anti-LDHA agent.

Therapeutic use of the dsRNA agents of the instant invention can involveuse of formulations of dsRNA agents comprising multiple different dsRNAagent sequences. For example, two or more, three or more, four or more,five or more, etc. of the presently described agents can be combined toproduce a formulation that, e.g., targets multiple different regions ofthe lactate dehydrogenase RNA, or that not only target lactatedehydrogenase RNA but also target, e.g., cellular target genesassociated with a lactate dehydrogenase-associated disease or disorder.A dsRNA agent of the instant invention may also be constructed such thateither strand of the dsRNA agent independently targets two or moreregions of lactate dehydrogenase RNA, or such that one of the strands ofthe dsRNA agent targets a cellular target gene of lactate dehydrogenaseknown in the art.

Use of multifunctional dsRNA molecules that target more then one regionof a target nucleic acid molecule can also provide potent inhibition oflactate dehydrogenase RNA levels and expression. For example, a singlemultifunctional dsRNA construct of the invention can target both thelactate dehydrogenase-402 and lactate dehydrogenase-723 sitessimultaneously; additionally and/or alternatively, single ormultifunctional agents of the invention can be designed to selectivelytarget one splice variant of lactate dehydrogenase over another.

Thus, the dsRNA agents of the instant invention, individually, or incombination or in conjunction with other drugs, can be used to treat,inhibit, reduce, or prevent a lactate dehydrogenase-associated diseaseor disorder. For example, the dsRNA molecules can be administered to asubject or can be administered to other appropriate cells evident tothose skilled in the art, individually or in combination with one ormore drugs under conditions suitable for the treatment.

The dsRNA molecules also can be used in combination with other knowntreatments to treat, inhibit, reduce, or prevent PH1 or other lactatedehydrogenase-associated disease or disorder in a subject or organism.For example, the described molecules could be used in combination withone or more known compounds, treatments, or procedures to treat,inhibit, reduce, or prevent PH1 or other lactatedehydrogenase-associated disease or disorder in a subject or organism asare known in the art.

A dsRNA agent of the invention can be conjugated (e.g., at its 5′ or 3′terminus of its sense or antisense strand) or unconjugated to anothermoiety (e.g. a non-nucleic acid moiety such as a peptide), an organiccompound (e.g., a dye, cholesterol, or the like). Modifying dsRNA agentsin this way may improve cellular uptake or enhance cellular targetingactivities of the resulting dsRNA agent derivative as compared to thecorresponding unconjugated dsRNA agent, are useful for tracing the dsRNAagent derivative in the cell, or improve the stability of the dsRNAagent derivative compared to the corresponding unconjugated dsRNA agent.

Methods of Introducing Nucleic Acids, Vectors, and Host Cells

dsRNA agents of the invention may be directly introduced into a cell(i.e., intracellularly); or introduced extracellularly into a cavity,interstitial space, into the circulation of an organism, introducedorally, or may be introduced by bathing a cell or organism in a solutioncontaining the nucleic acid. Vascular or extravascular circulation, theblood or lymph system, and the cerebrospinal fluid are sites where thenucleic acid may be introduced.

The dsRNA agents of the invention can be introduced using nucleic aciddelivery methods known in art including injection of a solutioncontaining the nucleic acid, bombardment by particles covered by thenucleic acid, soaking the cell or organism in a solution of the nucleicacid, or electroporation of cell membranes in the presence of thenucleic acid. Other methods known in the art for introducing nucleicacids to cells may be used, such as lipid-mediated carrier transport,chemical-mediated transport, and cationic liposome transfection such ascalcium phosphate, and the like. The nucleic acid may be introducedalong with other components that perform one or more of the followingactivities: enhance nucleic acid uptake by the cell or other-wiseincrease inhibition of the target lactate dehydrogenase RNA.

A cell having a target lactate dehydrogenase RNA may be from the germline or somatic, totipotent or pluripotent, dividing or non-dividing,parenchyma or epithelium, immortalized or transformed, or the like. Thecell may be a stem cell or a differentiated cell. Cell types that aredifferentiated include adipocytes, fibroblasts, myocytes,cardiomyocytes, endothelium, neurons, glia, blood cells, megakaryocytes,lymphocytes, macrophages, neutrophils, eosinophils, basophils, mastcells, leukocytes, granulocytes, keratinocytes, chondrocytes,osteoblasts, osteoclasts, hepatocytes, and cells of the endocrine orexocrine glands.

Depending on the particular target lactate dehydrogenase RNA sequenceand the dose of dsRNA agent material delivered, this process may providepartial or complete loss of function for the lactate dehydrogenase RNA.A reduction or loss of RNA levels or expression (either lactatedehydrogenase RNA expression or encoded polypeptide expression) in atleast 50%, 60%, 70%, 80%, 90%, 95% or 99% or more of targeted cells isexemplary. Inhibition of lactate dehydrogenase RNA levels or expressionrefers to the absence (or observable decrease) in the level of lactatedehydrogenase RNA or lactate dehydrogenase RNA-encoded protein.Specificity refers to the ability to inhibit the lactate dehydrogenaseRNA without manifest effects on other genes of the cell. Theconsequences of inhibition can be confirmed by examination of theoutward properties of the cell or organism or by biochemical techniquessuch as RNA solution hybridization, nuclease protection, Northernhybridization, reverse transcription, gene expression monitoring with amicroarray, antibody binding, enzyme linked immunosorbent assay (ELISA),Western blotting, radioimmunoassay (RIA), other immunoassays, andfluorescence activated cell analysis (FACS). Inhibition of targetlactate dehydrogenase RNA sequence(s) by the dsRNA agents of theinvention also can be measured based upon the effect of administrationof such dsRNA agents upon development/progression of PH1 or otherlactate dehydrogenase-associated disease or disorder, either in vivo orin vitro. Treatment of any of these conditions can be assessed byart-recognized tests for PH1 and/or kidney function, e.g., determinationof the percentage of kidney function and/or kidney stone formation(e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80% or greater) that is beingachieved relative to average healthy kidney function and/or stoneformation of an appropriate control population. In certain embodiments,successful treatment results in a decline or halting of stone formationor a decline or halting of reduction in total kidney function associatedwith PH1 or other lactate dehydrogenase-associated disease or disorder.In some embodiments, kidney function improves with successful treatment.

For RNA-mediated inhibition in a cell line or whole organism, expressiona reporter or drug resistance gene whose protein product is easilyassayed can be measured. Such reporter genes include acetohydroxyacidsynthase (AHAS), alkaline phosphatase (AP), beta galactosidase (LacZ),beta glucoronidase (GUS), chloramphenicol acetyltransferase (CAT), greenfluorescent protein (GFP), horseradish peroxidase (HRP), luciferase(Luc), nopaline synthase (NOS), octopine synthase (OCS), and derivativesthereof. Multiple selectable markers are available that conferresistance to ampicillin, bleomycin, chloramphenicol, gentarnycin,hygromycin, kanamycin, lincomycin, methotrexate, phosphinothricin,puromycin, and tetracyclin. Depending on the assay, quantitation of theamount of gene expression allows one to determine a degree of inhibitionwhich is greater than 10%, 33%, 50%, 90%, 95% or 99% as compared to acell not treated according to the present invention.

Lower doses of injected material and longer times after administrationof RNA silencing agent may result in inhibition in a smaller fraction ofcells (e.g., at least 10%, 20%, 50%, 75%, 90%, or 95% of targetedcells). Quantitation of gene expression in a cell may show similaramounts of inhibition at the level of accumulation of target lactatedehydrogenase RNA or translation of target protein. As an example, theefficiency of inhibition may be determined by assessing the amount ofgene product in the cell; RNA may be detected with a hybridization probehaving a nucleotide sequence outside the region used for the inhibitorydsRNA, or translated polypeptide may be detected with an antibody raisedagainst the polypeptide sequence of that region.

The dsRNA agent may be introduced in an amount which allows delivery ofat least one copy per cell. Higher doses (e.g., at least 5, 10, 100, 500or 1000 copies per cell) of material may yield more effectiveinhibition; lower doses may also be useful for specific applications.

Pharmaceutical Compositions

In certain embodiments, the present invention provides for apharmaceutical composition comprising the dsRNA agent of the presentinvention. The dsRNA agent sample can be suitably formulated andintroduced into the environment of the cell by any means that allows fora sufficient portion of the sample to enter the cell to induce genesilencing, if it is to occur. Many formulations for dsRNA are known inthe art and can be used so long as the dsRNA gains entry to the targetcells so that it can act. See, e.g., U.S. published patent applicationNos. 2004/0203145 A1 and 2005/0054598 A1. For example, the dsRNA agentof the instant invention can be formulated in buffer solutions such asphosphate buffered saline solutions, liposomes, micellar structures, andcapsids. Formulations of dsRNA agent with cationic lipids can be used tofacilitate transfection of the dsRNA agent into cells. For example,cationic lipids, such as lipofectin (U.S. Pat. No. 5,705,188), cationicglycerol derivatives, and polycationic molecules, such as polylysine(published PCT International Application WO 97/30731), can be used.Suitable lipids include Oligofectamine, Lipofectamine (LifeTechnologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.),or FuGene 6 (Roche) all of which can be used according to themanufacturer's instructions.

Such compositions typically include the nucleic acid molecule and apharmaceutically acceptable carrier. As used herein the language“pharmaceutically acceptable carrier” includes saline, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like, compatible withpharmaceutical administration. Supplementary active compounds can alsobe incorporated into the compositions.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. Examples of routes of administrationinclude parenteral, e.g., intravenous, intradermal, subcutaneous, oral(e.g., inhalation), transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It should be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in a selected solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules, e.g., gelatin capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer. Such methods include those described in U.S. Pat. No.6,468,798.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g.,with conventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

The compounds can also be administered by transfection or infectionusing methods known in the art, including but not limited to the methodsdescribed in McCaffrey et al. (2002), Nature, 418(6893), 38-9(hydrodynamic transfection); Xia et al. (2002), Nature Biotechnol.,20(10), 1006-10 (viral-mediated delivery); or Putnam (1996), Am. J.Health Syst. Pharm. 53(2), 151-160, erratum at Am. J. Health Syst.Pharm. 53(3), 325 (1996).

The compounds can also be administered by a method suitable foradministration of nucleic acid agents, such as a DNA vaccine. Thesemethods include gene guns, bio injectors, and skin patches as well asneedle-free methods such as the micro-particle DNA vaccine technologydisclosed in U.S. Pat. No. 6,194,389, and the mammalian transdermalneedle-free vaccination with powder-form vaccine as disclosed in U.S.Pat. No. 6,168,587. Additionally, intranasal delivery is possible, asdescribed in, inter alia, Hamajima et al. (1998), Clin. Immunol.Immunopathol., 88(2), 205-10. Liposomes (e.g., as described in U.S. Pat.No. 6,472,375) and microencapsulation can also be used. Biodegradabletargetable microparticle delivery systems can also be used (e.g., asdescribed in U.S. Pat. No. 6,471,996).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Suchformulations can be prepared using standard techniques. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions can also be used aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD/ED₅₀.Compounds which exhibit high therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For a compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

As defined herein, a therapeutically effective amount of a nucleic acidmolecule (i.e., an effective dosage) depends on the nucleic acidselected. For instance, single dose amounts of a dsRNA (or, e.g., aconstruct(s) encoding for such dsRNA) in the range of approximately 1 μgto 1000 mg may be administered; in some embodiments, 10, 30, 100, or1000 μg, or 10, 30, 100, or 1000 ng, or 10, 30, 100, or 1000 μg, or 10,30, 100, or 1000 mg may be administered. In some embodiments, 1-5 g ofthe compositions can be administered. The compositions can beadministered one from one or more times per day to one or more times perweek; including once every other day. The skilled artisan willappreciate that certain factors may influence the dosage and timingrequired to effectively treat a subject, including but not limited tothe severity of the disease or disorder, previous treatments, thegeneral health and/or age of the subject, and other diseases present.Moreover, treatment of a subject with a therapeutically effective amountof a nucleic acid (e.g., dsRNA), protein, polypeptide, or antibody caninclude a single treatment or, preferably, can include a series oftreatments.

The nucleic acid molecules of the invention can be inserted intoexpression constructs, e.g., viral vectors, retroviral vectors,expression cassettes, or plasmid viral vectors, e.g., using methodsknown in the art, including but not limited to those described in Xia etal., (2002), supra. Expression constructs can be delivered to a subjectby, for example, inhalation, orally, intravenous injection, localadministration (see U.S. Pat. No. 5,328,470) or by stereotacticinjection (see e.g., Chen et al. (1994), Proc. Natl. Acad. Sci. USA, 91,3054-3057). The pharmaceutical preparation of the delivery vector caninclude the vector in an acceptable diluent, or can comprise a slowrelease matrix in which the delivery vehicle is imbedded. Alternatively,where the complete delivery vector can be produced intact fromrecombinant cells, e.g., retroviral vectors, the pharmaceuticalpreparation can include one or more cells which produce the genedelivery system.

The expression constructs may be constructs suitable for use in theappropriate expression system and include, but are not limited toretroviral vectors, linear expression cassettes, plasmids and viral orvirally-derived vectors, as known in the art. Such expression constructsmay include one or more inducible promoters, RNA Pol III promotersystems such as U6 snRNA promoters or HI RNA polymerase III promoters,or other promoters known in the art. The constructs can include one orboth strands of the siRNA. Expression constructs expressing both strandscan also include loop structures linking both strands, or each strandcan be separately transcribed from separate promoters within the sameconstruct. Each strand can also be transcribed from a separateexpression construct, e.g., Tuschl (2002, Nature Biotechnol 20:500-505).

It can be appreciated that the method of introducing dsRNA agents intothe environment of the cell will depend on the type of cell and the makeup of its environment. For example, when the cells are found within aliquid, one preferable formulation is with a lipid formulation such asin lipofectamine and the dsRNA agents can be added directly to theliquid environment of the cells. Lipid formulations can also beadministered to animals such as by intravenous, intramuscular, orintraperitoneal injection, or orally or by inhalation or other methodsas are known in the art. When the formulation is suitable foradministration into animals such as mammals and more specificallyhumans, the formulation is also pharmaceutically acceptable.Pharmaceutically acceptable formulations for administeringoligonucleotides are known and can be used. In some instances, it may bepreferable to formulate dsRNA agents in a buffer or saline solution anddirectly inject the formulated dsRNA agents into cells, as in studieswith oocytes. The direct injection of dsRNA agent duplexes may also bedone. For suitable methods of introducing dsRNA (e.g., DsiRNA agents),see U.S. published patent application No. 2004/0203145 A1.

Suitable amounts of a dsRNA agent must be introduced and these amountscan be empirically determined using standard methods. Typically,effective concentrations of individual dsRNA agent species in theenvironment of a cell will be 50 nanomolar or less, 10 nanomolar orless, or compositions in which concentrations of 1 nanomolar or less canbe used. In another embodiment, methods utilizing a concentration of 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, and even a concentration of 10 picomolar or less, 5picomolar or less, 2 picomolar or less or 1 picomolar or less can beused in many circumstances.

The method can be carried out by addition of the dsRNA agentcompositions to an extracellular matrix in which cells can live providedthat the dsRNA agent composition is formulated so that a sufficientamount of the dsRNA agent can enter the cell to exert its effect. Forexample, the method is amenable for use with cells present in a liquidsuch as a liquid culture or cell growth media, in tissue explants, or inwhole organisms, including animals, such as mammals and especiallyhumans.

The level or activity of a lactate dehydrogenase RNA can be determinedby a suitable method now known in the art or that is later developed. Itcan be appreciated that the method used to measure a target RNA and/orthe expression of a target RNA can depend upon the nature of the targetRNA. For example, where the target lactate dehydrogenase RNA sequenceencodes a protein, the term “expression” can refer to a protein or thelactate dehydrogenase RNA/transcript derived from the lactatedehydrogenase gene (either genomic or of exogenous origin). In suchinstances the expression of the target lactate dehydrogenase RNA can bedetermined by measuring the amount of lactate dehydrogenaseRNA/transcript directly or by measuring the amount of lactatedehydrogenase protein. Protein can be measured in protein assays such asby staining or immunoblotting or, if the protein catalyzes a reactionthat can be measured, by measuring reaction rates. All such methods areknown in the art and can be used. Where target lactate dehydrogenase RNAlevels are to be measured, art-recognized methods for detecting RNAlevels can be used (e.g., RT-PCR, Northern Blotting, etc.). In targetinglactate dehydrogenase RNAs with the dsRNA agents of the instantinvention, it is also anticipated that measurement of the efficacy of adsRNA agent in reducing levels of lactate dehydrogenase RNA or proteinin a subject, tissue, in cells, either in vitro or in vivo, or in cellextracts can also be used to determine the extent of reduction of PH1,oxalate accumulation or other lactate dehydrogenase-associated diseaseor disorder phenotypes (e.g., kidney function, kidney stones, etc.). Theabove measurements can be made on cells, cell extracts, tissues, tissueextracts or other suitable source material.

The determination of whether the expression of a lactate dehydrogenaseRNA has been reduced can be by a suitable method that can reliablydetect changes in RNA levels. Typically, the determination is made byintroducing into the environment of a cell undigested dsRNA such that atleast a portion of that dsRNA agent enters the cytoplasm, and thenmeasuring the level of the target RNA. The same measurement is made onidentical untreated cells and the results obtained from each measurementare compared.

The dsRNA agent can be formulated as a pharmaceutical composition whichcomprises a pharmacologically effective amount of a dsRNA agent andpharmaceutically acceptable carrier. A pharmacologically ortherapeutically effective amount refers to that amount of a dsRNA agenteffective to produce the intended pharmacological, therapeutic orpreventive result. The phrases “pharmacologically effective amount” and“therapeutically effective amount” or simply “effective amount” refer tothat amount of an RNA effective to produce the intended pharmacological,therapeutic or preventive result. For example, if a given clinicaltreatment is considered effective when there is at least a 20% reductionin a measurable parameter associated with a disease or disorder, atherapeutically effective amount of a drug for the treatment of thatdisease or disorder is the amount necessary to effect at least a 20%reduction in that parameter.

Suitably formulated pharmaceutical compositions of this invention can beadministered by means known in the art such as by parenteral routes,including intravenous, intramuscular, intraperitoneal, subcutaneous,transdermal, airway (aerosol), rectal, vaginal and topical (includingbuccal and sublingual) administration. In some embodiments, thepharmaceutical compositions are administered by intravenous orintraparenteral infusion or injection.

In general, a suitable dosage unit of dsRNA will be in the range of0.001 to 0.25 milligrams per kilogram body weight of the recipient perday, or in the range of 0.01 to 20 micrograms per kilogram body weightper day, or in the range of 0.001 to 5 micrograms per kilogram of bodyweight per day, or in the range of 1 to 500 nanograms per kilogram ofbody weight per day, or in the range of 0.01 to 10 micrograms perkilogram body weight per day, or in the range of 0.10 to 5 microgramsper kilogram body weight per day, or in the range of 0.1 to 2.5micrograms per kilogram body weight per day. A pharmaceuticalcomposition comprising the dsRNA can be administered once daily.However, the therapeutic agent may also be dosed in dosage unitscontaining two, three, four, five, six or more sub-doses administered atappropriate intervals throughout the day. In that case, the dsRNAcontained in each sub-dose must be correspondingly smaller in order toachieve the total daily dosage unit. The dosage unit can also becompounded for a single dose over several days, e.g., using aconventional sustained release formulation which provides sustained andconsistent release of the dsRNA over a several day period. Sustainedrelease formulations are well known in the art. In this embodiment, thedosage unit contains a corresponding multiple of the daily dose.Regardless of the formulation, the pharmaceutical composition mustcontain dsRNA in a quantity sufficient to inhibit expression of thetarget gene in the animal or human being treated. The composition can becompounded in such a way that the sum of the multiple units of dsRNAtogether contain a sufficient dose.

Data can be obtained from cell culture assays and animal studies toformulate a suitable dosage range for humans. The dosage of compositionsof the invention lies within a range of circulating concentrations thatinclude the ED₅₀ (as determined by known methods) with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For acompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range of the compound that includes the IC₅₀ (i.e., theconcentration of the test compound which achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsof dsRNA in plasma may be measured by standard methods, for example, byhigh performance liquid chromatography.

The pharmaceutical compositions can be included in a kit, container,pack, or dispenser together with instructions for administration.

Formulations can give trophism, and there are certain benefits to that.Specificity of LDHA, LDHB, LDHC are advantageous. [[Back off ofstatements re tissue specificity—what if delivery to muscle does notimpact negatively]].

Methods of Treatment

The present invention provides for both prophylactic and therapeuticmethods of treating a subject at risk of (or susceptible to) a diseaseor disorder caused, in whole or in part, by lactate dehydrogenase (e.g.,misregulation and/or elevation of lactate dehydrogenase transcriptand/or lactate dehydrogenase protein levels), or treatable via selectivetargeting of lactate dehydrogenase.

In certain aspects, the invention provides a method for preventing in asubject, a disease or disorder as described herein (including, e.g.,prevention of PH1 within a subject via inhibition of lactatedehydrogenase expression), by administering to the subject a therapeuticagent (e.g., a dsRNA agent or vector or transgene encoding same).Subjects at risk for the disease can be identified by, for example, oneor a combination of diagnostic or prognostic assays known in the art(e.g., identification of reduced functionality of AGT, or other alteredfunctioning of the oxalate-producing pathway, in a subject).Administration of a prophylactic agent can occur prior to the detectionof, e.g., PH1 in a subject, or the manifestation of symptomscharacteristic of the disease or disorder, such that the disease ordisorder is prevented or, alternatively, delayed in its progression.

Another aspect of the invention pertains to methods of treating subjectstherapeutically, i.e., altering the onset of symptoms of the disease ordisorder. These methods can be performed in vitro (e.g., by culturingthe cell with the dsRNA agent) or, alternatively, in vivo (e.g., byadministering the dsRNA agent to a subject).

With regard to both prophylactic and therapeutic methods of treatment,such treatments may be specifically tailored or modified, based onknowledge obtained from the field of pharmacogenomics.“Pharmacogenomics”, as used herein, refers to the application ofgenomics technologies such as gene sequencing, statistical genetics, andgene expression analysis to drugs in clinical development and on themarket. More specifically, the term refers the study of how a patient'sgenes determine his or her response to a drug (e.g., a patient's “drugresponse phenotype”, or “drug response genotype”). Thus, another aspectof the invention provides methods for tailoring an individual'sprophylactic or therapeutic treatment with either the target lactatedehydrogenase RNA molecules of the present invention or target lactatedehydrogenase RNA modulators according to that individual's drugresponse genotype. Pharmacogenomics allows a clinician or physician totarget prophylactic or therapeutic treatments to patients who will mostbenefit from the treatment and to avoid treatment of patients who willexperience toxic drug-related side effects.

The practice of the present invention employs, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA, genetics, immunology, cell biology, cellculture and transgenic biology, which are within the skill of the art.See, e.g., Maniatis et al., 1982, Molecular Cloning (Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y.); Sambrook et al., 1989,Molecular Cloning, 2nd Ed. (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Sambrook and Russell, 2001, Molecular Cloning, 3rdEd. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.);Ausubel et al., 1992), Current Protocols in Molecular Biology (JohnWiley & Sons, including periodic updates); Glover, 1985, DNA Cloning(IRL Press, Oxford); Anand, 1992; Guthrie and Fink, 1991; Harlow andLane, 1988, Antibodies, (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Jakoby and Pastan, 1979; Nucleic AcidHybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription AndTranslation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of AnimalCells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells AndEnzymes (IRL Press, 1986); B. Perbal, A Practical Guide To MolecularCloning (1984); the treatise, Methods In Enzymology (Academic Press,Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller andM. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods InEnzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical MethodsIn Cell And Molecular Biology (Mayer and Walker, eds., Academic Press,London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M.Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6thEdition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al.,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986); Westerfield, M., The zebrafish book. Aguide for the laboratory use of zebrafish (Danio rerio), (4th Ed., Univ.of Oregon Press, Eugene, 2000).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Examples

The present invention is described by reference to the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below were utilized.

Example 1: Preparation of Double-Stranded RNA Oligonudeotides

Oligonucleotide Synthesis and Purification

DsiRNA molecules can be designed to interact with various sites in theRNA message, for example, target sequences within the RNA sequencesdescribed herein. In presently exemplified agents, 48 DsiRNAs predictedon the basis of homology to uniquely target human lactate dehydrogenase(LDHA) sequences, 48 DsiRNAs predicted on the basis of homology touniquely target mouse lactate dehydrogenase sequences, and an additional24 DsiRNAs predicted to target both human and mouse lactatedehydrogenase sequences were selected for evaluation. The sequences ofone strand of the DsiRNA molecules were complementary to target lactatedehydrogenase site sequences. The DsiRNA molecules were chemicallysynthesized using methods described herein. Generally, DsiRNA constructswere synthesized using solid phase oligonucleotide synthesis methods asdescribed for 19-23mer siRNAs (see for example Usman et al., U.S. Pat.Nos. 5,804,683; 5,831,071; 5,998,203; 6,117,657; 6,353,098; 6,362,323;6,437,117; 6,469,158; Scaringe et al., U.S. Pat. Nos. 6,111,086;6,008,400; 6,111,086).

Individual RNA strands were synthesized and HPLC purified according tostandard methods (Integrated DNA Technologies, Coralville, Iowa). Forexample, RNA oligonucleotides were synthesized using solid phasephosphoramidite chemistry, deprotected and desalted on NAP-5 columns(Amersham Pharmacia Biotech, Piscataway, N.J.) using standard techniques(Damha and Olgivie, 1993, Methods Mol Biol 20: 81-114; Wincott et al.,1995, Nucleic Acids Res 23: 2677-84). The oligomers were purified usingion-exchange high performance liquid chromatography (IE-HPLC) on anAmersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech,Piscataway, N.J.) using a 15 min step-linear gradient. The gradientvaried from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A was100 mM Tris pH 8.5 and Buffer B was 100 mM Tris pH 8.5, 1 M NaCl.Samples were monitored at 260 nm and peaks corresponding to thefull-length oligonucleotide species were collected, pooled, desalted onNAP-5 columns, and lyophilized.

The purity of each oligomer was determined by capillary electrophoresis(CE) on a Beckman PACE 5000 (Beckman Coulter, Inc., Fullerton, Calif.).The CE capillaries had a 100 μm inner diameter and contained ssDNA 100RGel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide wasinjected into a capillary, run in an electric field of 444 V/cm anddetected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urearunning buffer was purchased from Beckman-Coulter. Oligoribonucleotideswere obtained that were at least 90% pure as assessed by CE for use inexperiments described below. Compound identity was verified bymatrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)mass spectroscopy on a Voyager DE™. Biospectometry Work Station (AppliedBiosystems, Foster City, Calif.) following the manufacturer'srecommended protocol. Relative molecular masses of all oligomers wereobtained, often within 0.2% of expected molecular mass.

Preparation of Duplexes

Single-stranded RNA (ssRNA) oligomers were resuspended, e.g., at 100 μMconcentration in duplex buffer consisting of 100 mM potassium acetate,30 mM HEPES, pH 7.5. Complementary sense and antisense strands weremixed in equal molar amounts to yield a final solution of, e.g., 50 μMduplex. Samples were heated to 100° C. for 5′ in RNA buffer (IDT) andallowed to cool to room temperature before use. Double-stranded RNA(dsRNA) oligomers were stored at −20° C. Single-stranded RNA oligomerswere stored lyophilized or in nuclease-free water at −80° C.

Nomenclature

For consistency, the following nomenclature has been employed in theinstant specification. Names given to duplexes indicate the length ofthe oligomers and the presence or absence of overhangs. A “25/27” is anasymmetric duplex having a 25 base sense strand and a 27 base antisensestrand with a 2-base 3′-overhang. A “27/25” is an asymmetric duplexhaving a 27 base sense strand and a 25 base antisense strand.

Cell culture and RNA Transfection

HeLa cells were obtained and maintained in DMEM (HyClone) supplementedwith 10% fetal bovine serum (HyClone) at 37° C. under 5% CO₂. For RNAtransfections, cells were transfected with DsiRNAs at a finalconcentration of 1 nM, 0.1 nM or 0.03 nM using Lipofectamine™ RNAiMAX(Invitrogen) and following manufacturer's instructions. Briefly, for 0.1nM transfections, e.g., of Example 3 below, an aliquot of stock solutionof each DsiRNA was mixed with Opti-MEM I (Invitrogen) and Lipofectamine™RNAiMAX to reach a volume of 150 μL (with 0.3 nM DsiRNA). The resulting150 μL mix was incubated for 20 min at RT to allow DsiRNA:Lipofectamine™RNAiMAX complexes to form. Meanwhile, target cells were trypsinized andresuspended in medium. At the end of the 20 min of complexation, 50 uLof the DsiRNA:RNAiMAX mixture was added per well into triplicate wellsof 96 well plates. Finally, 100 μL of the cell suspension was added toeach well (final volume 150 μL) and plates were placed into theincubator for 24 hours.

Assessment of LDHA Inhibition

Lactate Dehydrogenase target gene knockdown was determined by qRT-PCR,with values normalized to HPRT and SFRS9 housekeeping genes, and totransfections with control DsiRNAs and/or mock transfection controls.

RNA isolation and analysis

Media was aspirated, and total RNA was extracted using the SV96 kit(Promega). Total RNA was reverse-transcribed using SuperscriptII, OligodT, and random hexamers following manufacturer's instructions.Typically, the resulting cDNA was analyzed by qPCR using primers andprobes specific for both the lactate dehydrogenase gene and for thehuman genes HPRT-1 and SFRS9. An ABI 7700 was used for the amplificationreactions. Each sample was tested in triplicate. Relative LDHA RNAlevels were normalized to HPRT1 and SFRS9 RNA levels and compared withRNA levels obtained in transfection control samples.

Example 2: DsiRNA Inhibition of LDHA

DsiRNA molecules targeting LDHA were designed and synthesized asdescribed above and tested in human HeLa cells (alternatively, HepG2 orother human cells could have been used) and/or mouse B16-F10 cells forinhibitory efficacy. For transfection, annealed DsiRNAs were mixed withthe transfection reagent (Lipofectamine™ RNAiMAX, Invitrogen) andincubated for 20 minutes at room temperature. The HeLa (human) orB16-F10 (mouse) cells (alternatively, mouse Hepa 1-6 or other mousecells could have been used) were trypsinized, resuspended in media, andadded to wells (100 uL per well) to give a final DsiRNA concentration of1 nM in a volume of 150 μl. Each DsiRNA transfection mixture was addedto 3 wells for triplicate DsiRNA treatments. Cells were incubated at 37°C. for 24 hours in the continued presence of the DsiRNA transfectionmixture. At 24 hours, RNA was prepared from each well of treated cells.The supernatants with the transfection mixtures were first removed anddiscarded, then the cells were lysed and RNA was prepared from eachwell. Target LDHA RNA levels following treatment were evaluated byqRT-PCR for the LDHA target gene, with values normalized to thoseobtained for controls. Triplicate data was averaged and the % error wasdetermined for each treatment. Normalized data were both tablulated andgraphed, and the reduction of target mRNA by active DsiRNAs incomparison to controls was determined (see Table 13 below and FIGS. 3Ato 3J).

TABLE 13 LDHA Inhibitory Efficacy of DsiRNAs Assayed at 1 nM in HumanHeLa and Mouse B16-F10 Cells Human - HeLa Mouse - B16-F10 NormalizedHPRT/SFRS9; Normalized HPRT/Rpl23; vs NC1, NC5, NC7 vs NC1, NC5, NC7 Hs262- Hs 1304- Mm 384- Mm 1402- 396 (FAM) 1419 (HEX) 510 (FAM) 1504(HEX)Duplex Mm Rhesus Assay Assay Assay Assay Name Location Location %Remaining % Remaining % Remaining % Remaining LDHA-355  440  2.7 ± 17.5 2.8 ± 14.8 LDHA-356  441 2.6 ± 8.5 2.6 ± 9.6 LDHA-397  482  8.5 ± 12.5 8.8 ± 11.1 LDHA-398  483  2.8 ± 11.5  3.1 ± 12.4 LDHA-739  824  8.7 ±19.5  9.0 ± 17.6 LDHA-740  825  3.9 ± 11.6  3.7 ± 13.2 LDHA-891  976 3.9± 7.0 3.8 ± 7.5 LDHA-892  977 2.5 ± 5.3 2.4 ± 3.8 LDHA-907  992 4.4 ±8.1 4.1 ± 8.5 LDHA-952  1037 2.9 ± 3.4 2.8 ± 6.0 LDHA-1286 1371  3.7 ±11.1 3.6 ± 2.7 LDHA-1287 1372 2.0 ± 2.2 1.9 ± 4.1 LDHA-1292 1377 4.3 ±2.0 4.3 ± 5.9 LDHA-1293 1378 2.2 ± 5.6 1.7 ± 1.6 LDHA-1294 1379 5.2 ±4.3 5.2 ± 3.1 LDHA-1359 1444 4.5 ± 2.4 3.5 ± 3.2 LDHA-1360 1445 3.8 ±9.4  3.2 ± 10.4 LDHA-1361 1446 3.0 ± 8.1 2.4 ± 8.7 LDHA-1362 1447 6.1 ±5.0 5.1 ± 5.0 LDHA-1363 1448 2.5 ± 2.5 2.0 ± 4.4 LDHA-1365 1450 3.3 ±1.2 2.7 ± 1.8 LDHA-1366 1451 3.4 ± 3.5 2.8 ± 2.6 LDHA-1367 1452 5.8 ±1.5 5.3 ± 1.7 LDHA-1368 1453 4.5 ± 6.8 3.5 ± 8.7 LDHA-1370 1455 7.3 ±7.0 6.3 ± 8.7 LDHA-1371 1456 2.5 ± 4.2 1.7 ± 7.4 LDHA-1372 1457 2.6 ±6.6 1.9 ± 9.1 LDHA-1393 1478 9.1 ± 2.5 2.0 ± 5.9 LDHA-1427 1512 8.7 ±3.1 3.6 ± 7.7 LDHA-1428 1513 8.5 ± 3.2  4.0 ± 12.3 LDHA-1512 1597 7.8 ±2.0 4.4 ± 3.6 LDHA-1513 1598 9.4 ± 4.4 5.7 ± 4.1 LDHA-1514 1599 7.0 ±1.7 3.7 ± 1.7 LDHA-1516 1601 6.7 ± 4.3 3.7 ± 5.3 LDHA-1684 1760  3.9 ±10.4  1.7 ± 14.2 LDHA-1688 1764 4.7 ± 1.9 2.6 ± 3.6 LDHA-1736 1814 11.4± 0.6  8.3 ± 1.2 LDHA-1750 1832 3.9 ± 2.5 2.1 ± 3.6 LDHA-1753 1835 6.5 ±1.4 3.2 ± 3.9 LDHA-1754 1836 8.0 ± 3.9 4.3 ± 4.8 LDHA-1805 1887 6.3 ±6.9 3.3 ± 4.2 LDHA-1806 1888 6.4 ± 4.2 3.6 ± 4.9 LDHA-1807 1889 9.5 ±2.4 7.6 ± 2.3 LDHA-1808 1890 5.7 ± 2.9 3.0 ± 3.4 LDHA-1811 1893 6.4 ±2.8 2.9 ± 3.8 LDHA-1812 1894 5.9 ± 1.9 3.1 ± 1.9 LDHA-1815 1897 7.3 ±3.4 4.0 ± 4.2 LDHA-1816 1898 12.2 ± 5.4  8.5 ± 6.7 LDHA-360  419 445 7.2± 4.2 7.4 ± 3.3 11.2 ± 4.3  8.8 ± 8.0 LDHA-361  420 446  3.5 ± 12.0  3.7± 14.2 6.3 ± 9.0  4.5 ± 10.9 LDHA-362  421 447 8.4 ± 9.8 10.0 ± 9.2 11.6 ± 16.0  8.5 ± 14.0 LDHA-363  422 448 20.5 ± 11.3 23.3 ± 10.4 26.0 ±7.4  19.4 ± 11.5 LDHA-364  423 449  7.6 ± 17.3  7.7 ± 15.5 14.1 ± 25.3 9.9 ± 19.4 LDHA-365  424 450 10.4 ± 13.0 11.0 ± 10.5 13.1 ± 18.0  8.5 ±14.3 LDHA-366  425 451 15.0 ± 2.2  22.1 ± 2.5  12.6 ± 6.8  11.8 ± 2.9 LDHA-367  426 452 7.8 ± 7.6 9.1 ± 8.6 9.7 ± 5.5 9.4 ± 4.6 LDHA-369  428454 23.7 ± 4.3  24.5 ± 3.0  12.7 ± 6.1  11.3 ± 5.1  LDHA-370  429 4555.9 ± 2.5 5.8 ± 2.2 6.1 ± 5.1 5.0 ± 9.5 LDHA-399  458 484 3.0 ± 4.9  3.3± 11.1 7.3 ± 7.8  7.4 ± 28.4 LDHA-400  459 485 7.7 ± 6.2 8.4 ± 6.2 13.9± 1.2  10.2 ± 4.6  LDHA-401  460 486 4.1 ± 6.1 4.1 ± 5.2 8.5 ± 1.8 5.5 ±1.9 LDHA-402  461 487 2.6 ± 5.7 3.0 ± 4.1 4.3 ± 5.8 3.0 ± 7.0 LDHA-403 462 488 7.2 ± 3.4 7.2 ± 2.0 8.7 ± 4.4 7.3 ± 4.0 LDHA-404  463 489 15.7 ±4.1  14.7 ± 5.9  14.0 ± 7.7  10.8 ± 5.7  LDHA-714  773 799  7.9 ± 11.0 8.4 ± 11.3 10.8 ± 3.0  9.2 ± 8.8 LDHA-717  776 802 6.2 ± 1.4 7.4 ± 1.09.8 ± 7.7 8.7 ± 1.1 LDHA-718  777 803 1.8 ± 7.8 2.0 ± 5.1 2.6 ± 6.8 3.7± 6.0 LDHA-719  778 804 2.4 ± 1.9 2.7 ± 3.6 3.4 ± 3.0 3.3 ± 3.2LDHA-720  779 805 3.6 ± 5.5 3.6 ± 3.0 6.0 ± 3.2 5.1 ± 4.6 LDHA-722  781807 9.6 ± 2.2 10.7 ± 1.5  29.3 ± 36.2 13.8 ± 10.4 LDHA-723  782 808 3.1± 5.7 3.1 ± 4.5 2.1 ± 7.8 2.6 ± 6.9 LDHA-724  783 809 7.1 ± 6.4  7.4 ±10.1 8.1 ± 7.9 7.1 ± 9.6 LDHA-m367  6.7 ± 9.9  6.4 ± 11.1 LDHA-m368  3.7 ± 15.8  3.4 ± 11.2 LDHA-m372   6.0 ± 23.0  5.3 ± 14.6 LDHA-m376 4.8 ± 1.9 4.5 ± 0.1 LDHA-m456  38.3 ± 10.4 29.6 ± 10.4 LDHA-m501  3.3 ±5.3  3.9 ± 12.5 LDHA-m506  17.3 ± 10.4 15.1 ± 11.5 LDHA-m507  17.4 ±5.1  14.4 ± 5.5  LDHA-m584   5.9 ± 11.4 6.2 ± 6.0 LDHA-m689  2.3 ± 5.03.0 ± 4.1 LDHA-m694  2.1 ± 2.0 2.7 ± 3.0 LDHA-m695  6.9 ± 1.6 6.0 ± 2.5LDHA-m823  3.6 ± 4.4 4.5 ± 3.1 LDHA-m1071 4.5 ± 4.6 3.6 ± 4.0 LDHA-m11332.8 ± 6.3 3.0 ± 5.5 LDHA-m1183 6.5 ± 8.0 5.8 ± 7.6 LDHA-m1245 4.9 ± 8.04.7 ± 3.0 LDHA-m1250 5.8 ± 4.2 5.5 ± 4.6 LDHA-m1257 1.7 ± 7.1 6.6 ± 4.0LDHA-m1687 29.7 ± 9.2  24.6 ± 10.5 LDHA-m1688 5.6 ± 4.0 4.7 ± 5.2LDHA-m1690 12.9 ± 1.4  8.7 ± 1.7 LDHA-m1691 4.2 ± 6.7 3.6 ± 4.0LDHA-m1692 10.8 ± 4.8  9.7 ± 6.4 LDHA-m1694 37.2 ± 3.3  33.4 ± 2.5 LDHA-m1695  9.8 ± 16.0  7.3 ± 16.4 LDHA-m1697  3.6 ± 11.1  3.3 ± 12.3LDHA-m1698  6.6 ± 16.9  5.4 ± 18.8 LDHA-m1699 12.3 ± 5.9  8.5 ± 4.8LDHA-m1700  3.1 ± 17.6  2.4 ± 14.4 LDHA-m1701 2.1 ± 6.8 1.9 ± 5.6LDHA-m1702 4.2 ± 6.2 3.3 ± 3.4 LDHA-m1703 5.2 ± 4.4 4.5 ± 3.3 LDHA-m17046.7 ± 6.2 5.4 ± 5.3 LDHA-m1705 11.5 ± 12.8  9.3 ± 14.7 LDHA-m1706 13.6 ±3.5  10.7 ± 2.9  LDHA-m1707 2.8 ± 6.9 2.3 ± 4.8 LDHA-m1708 3.1 ± 5.0 2.5± 3.2 LDHA-m1709 2.2 ± 2.1 1.8 ± 3.2 LDHA-m1710  4.1 ± 10.0 3.3 ± 9.9LDHA-m1739  2.9 ± 11.2 2.5 ± 6.3 LDHA-m1743 3.8 ± 7.9 3.2 ± 7.6LDHA-m1744 2.2 ± 6.5 2.1 ± 4.0 LDHA-m1746 2.5 ± 1.8 2.2 ± 3.1 LDHA-m17512.5 ± 1.4 1.9 ± 3.0 LDHA-m1752 4.3 ± 6.0 3.0 ± 4.9 LDHA-m1755 2.9 ± 3.42.4 ± 3.4 LDHA-m1756 3.0 ± 4.6 2.6 ± 7.0

Example 3: Lactate Dehydrogenase-Targeting DsiRNAs were EffectiveInhibitors of Both LDHA mRNA and Protein In Vivo

The efficacy of LDHA-targeting DsiRNAs to inhibit both LDHA mRNA andprotein levels was examined in mice. As shown in FIGS. 4A to 4C,LDHA-targeting DsiRNAs potently inhibited mRNA and protein expression inmouse liver (human-mouse cross-reactive DsiRNAs LDHA-402, LDHA-723 andLDHA-370 possessing M107/M48 modifications were tested for mRNAknockdown, while LDHA-402 protein levels are shown in the right panel ofFIG. 4A, relative to a GAPDH control). Specifically, robust knockdown ofLDHA mRNA levels was observed at 24 hours post-DsiRNA injection.Meanwhile dramatically reduced levels of LDHA protein were observed inmice administered LDHA-402 DsiRNA, even at 14 days post-i.v. injectionat 1 mg/kg.

Example 4: Lactate Dehydrogenase-Targeting DsiRNAs DemonstratedPhenotypic Efficacy in Reducing Oxalate Excretion and in PreventingEthylene Glycol-Induced Kidney Damage and Calcium Oxalate Crystals inPH1 Model Mice

The ability of active lactate dehydrogenase-targeting DsiRNAs to reducelactate dehydrogenase levels within a mouse model of PH1 was examined,with the specific model employed relying upon pre-treatment of mice withAGXT-targeting DsiRNA (administered with timing of the upper arrows ofFIGS. 5A through 5D; alternatively, an AGXT knockout mouse, as describedin Hernandez-Fernaud and Salido (FEBS Journal 277: 4766-74) or othermodel of PH1 or other oxalate accumulation disease could have beenused).

Animals were randomized and assigned to groups based on marker levels.Dosing of animals with lipid nanoparticles (LNPs) containing indicatedDsiRNAs (an LNP formulation named EnCore-2072 was employed) wasperformed. Animals were dosed at 5 mg/kg iv, at indicated time points(upper arrows being AGXT DsiRNA injections or PBS, while lower arrowsindicate LDHA DsiRNA injections, PBS injections, PRODH2 DsiRNAinjections or HAO1 DsiRNA injections, as noted in each panel of FIG.5A). Animals were assayed for oxalate excretion levels, where reductionof oxalate excretion was indicative of an amelioration/reduction of PH1symptoms. As shown in FIGS. 5A through 5D, intravenous injection ofLDHA-targeting DsiRNA reduced oxalate excretion in PH1 model mice (micepre-treated with AGXT DsiRNA to simulate PH1), as compared toPBS-injected control PH1 model mice, and even as compared to PH1 modelmice administered DsiRNAs targeting oxalate metabolism pathwaycomponents glycolate oxidase (HAO1) or PRODH2 (proline dehydrogenase(oxidase) 2; see FIG. 6). In each of FIGS. 5A through 5D, mice(n=5/group) were injected on day 0 and day 14 with AGXT-targeting DsiRNA(upper arrows of each series). For results presented in FIGS. 5B and 5D,administration of AGXT-targeting DsiRNA was additionally performed ondays 28, 35 and 42. Mice treated with AGXT-targeting DsiRNA were thensubjected to intravenous injection of PBS (filled circles of FIGS. 5A to5D, upper left panels of FIGS. 5A and 5D), anti-PRODH2 DsiRNA (filledsquares of FIGS. 5A to 5D, upper right panels of FIGS. 5A and 5D),anti-HAO1 DsiRNA (filled diamonds of FIGS. 5A to 5D, lower left panel ofFIG. 5A; lower right panel of FIG. 5D) or anti-LDHA DsiRNA (filledtriangles of FIGS. 5A to 5D, lower right panel of FIG. 5A; lower leftpanel of FIG. 5D), respectively, at days 3, 10, 17 and 24, with FIGS. 5Band 5D showing the impact of additional administrations of such DsiRNAsat days 31 and 38 (anti-PRODH2 DsiRNA) or at day 38 (anti-LDHA DsiRNA oranti-HAO1 DsiRNA). In FIGS. 5A and 5C, oxalate excretion was measured atdays 0, 7 and 14 for PBS-treated PH1 model mice, while levels of oxalateexcretion were assayed in DsiRNA-treated mice at days −4, 7, 14, 21 and28. As shown in FIGS. 5B and 5D, extension of the studies respectivelyshown in FIGS. 5A and 5C was performed, with measurements of levels ofoxalate excretion in DsiRNA-treated mice also performed at days 37 and44. Both PBS- and PRODH2 DsiRNA-treated groups of mice were observed toexhibit dramatically elevated oxalate excretion levels when assayed atday 7 post-AGXT DsiRNA injection. PRODH2 DsiRNA-treated groups of micewere also observed to exhibit further elevated oxalate excretion levelswhen assayed at day 21 post-initial AGXT DsiRNA injection (whilePBS-treated mice were only maintained until day 14; FIG. 5A). HAO1DsiRNA-treated groups of mice were also observed to exhibit elevatedoxalate excretion levels when assayed at day 7 or day 21 post-initialAGXT DsiRNA injection, though the levels of such elevations appeared tobe reduced as compared to PBS-treated or PRODH2 DsiRNA-treated PH1 modelmice (FIG. 5A). These results largely persisted through extendedassessments; however, anti-HAO1 DsiRNA treatment more closely resembledanti-LDHA DsiRNA treatment at extended timepoints (FIG. 5B).

Remarkably, treatment of PH1 model mice with an LDHA-targeting DsiRNAunder the same injection schedule described above (LDHA-402-M107/M48DsiRNA in LNP 2185, administered by intravenous injection, whereAGXT-m1533-M107/M48 in LNP 2185 was also administered by intravenousinjection, at 1 mg/kg) revealed dramatic inhibitions of oxalateelevation at day 7, day 21 and later timepoints post-initial AGXT DsiRNAinjection. Thus, reduced levels of LDHA mRNA and protein (asdemonstrated in FIGS. 4A to 4C above) also translated into phenotypiceffects in inhibiting elevation of oxalate excretion in PH1 model mice.FIGS. 5C and 5D show that all DsiRNAs tested in PH1 model mice (PRODH2-,HAO1- and LDHA-targeting DsiRNAs) showed at least some inhibitory impactupon oxalate concentration (e.g., left panel of FIG. 5C). However,LDHA-targeting DsiRNA demonstrated the greatest reduction of oxalateexcretion, even as compared to HAO1-targeting DsiRNA. Such resultsindicated that reduction of oxalate concentration was necessary but notsufficient to observe downregulation of oxalate excretion.

The impact of anti-LDHA DsiRNA treatment of Agxt^(−/−) mice was assessedafter challenge with ethylene glycol (a PH1 model). As shown in FIG. 5E,when Agxt^(−/−) mice were challenged with ethylene glycol, LDHA DsiRNAadministration (specifically, LDHA-718-M24/M527 (DP2685P:DP2692G) in2185 LNP) was observed to reduce urine oxalate levels. As shown in FIGS.5F and 5G, administration of LDHA DsiRNA (LDHA-718-M24/M527(DP2685P:DP2692G) in 2185 LNP) was observed to prevent ethyleneglycol-induced kidney damage and prevent ethylene glycol-induced calciumoxalate crystals in Agxt^(−/−) mice.

Thus, in vivo results in PH1 model mice confirmed LDHA as a promisingtherapeutic target for gene silencing approaches (e.g., RNAiapproaches), not only for PH1 but also for all types of PH.

Example 5: Lactate Dehydrogenase-Targeting DsiRNAs Also EffectivelyReduced Urine Oxalate Levels in PH2 Model Mice

A mouse model of PH2 was produced via DsiRNA-mediated knockdown of Grhpr(refer to FIG. 6 for role of Grhpr). To examine the efficacy ofanti-LDHA DsiRNA treatment of PH2 in the PH2 model system, as well as toassess whether anti-LDHA DsiRNA treatment would exert a more pronouncedimpact upon PH2 than DsiRNAs targeting other components of theglyoxylate/oxalate pathway, anti-LDHA DsiRNA injection was compared withanti-PRODH2 DsiRNA injection and anti-HAO1 DsiRNA injection. As shown inFIG. 5H, intravenous injection of LDHA-targeting DsiRNA significantlyreduced urine oxalate levels in PH2 model mice, in contrast to HAO1- andPRODH2-targeting DsiRNAs, which did not reduce urinary oxalate levels inthe PH2 model mice. Thus, anti-LDHA DsiRNA treatment of PH2 wasespecially effective as compared to DsiRNAs targeting other componentsof the glyoxylate/oxalate pathway.

Example 6: Efficacy of Tetraloop-Extended Forms of LDHA-Targeting DicerSubstrates

A selection of active DsiRNAs identified in the above Examples were usedto synthesize corresponding tetraloop-possessing forms of such Dicersubstrate molecules. FIG. 7A shows tetraloop sequences and modificationpatterns employed in such experiments. This mini-set of fourmodification and tetraloop-possessing construct structures had beenvalidated for in vivo efficacy in HAO1-targeting constructs. Theidentified modification patterns and tetraloop-containing constructswere synthesized for DsiRNAs LDHA-718 (possessing a target sequencecommon to humans, rhesus and mouse, with respective tetraloop-containingpassenger and guide strand sequences of SEQ ID NOs: 7214 and 7215),LDHA-723 (possessing a target sequence common to humans, rhesus andmouse) and LDHA-1360 (possessing a target sequence common to humans andrhesus).

In vitro activities of the tetraloop constructs were examined in HeLacells. As shown in FIG. 7B, the “M576/M491” modification pattern DsiRNAspossessing tetraloop sequences were identified as having robust LDHAknockdown properties in vitro across each of LDHA-718, LDHA-723 andLDHA-1360 targets, with approximately 50% or greater knockdown observedfor LDHA-723 and LDHA-1360 constructs even at extremely low (0.01 nM)concentrations. As shown in FIG. 7C, dose-response curves were alsoobtained for tetraloop-possessing constructs derived from LDHA-723 andLDHA-1360 DsiRNAs. IC₅₀ values were calculated, and robusttetraloop-possessing LDHA-723 and LDHA-1360 structures were identified.The LDHA-723-M576/M491 modified tetraloop agent, identified to have anIC₅₀ of 20 pM, was selected for scale-up and conjugation (e.g., toGalNAc moieties), as it was potent and stable. It was also noted thatthe LDHA-1360 (possessing a target sequence common to humans and rhesus)tetraloop construct tolerated all modification patterns.

A broader screen for tetraloop-possessing agents that were both activeand stable was also performed. In such experiments, previouslyunmodified residues within 25/27mer modification patterns were convertedto 2′-F-modified residues, phosphorothioate linkages and tetraloopstructures were added, in a “2′-F fill tetraloop screen”. One goal ofsuch a screen was to use 2′-O-Methyl modification pattern screeningresults to derive potent and stable LDHA tetraloop constructs. To thisend, the most active 2′-O-methyl modification patterns for LDHA-718 werefilled in with 2′-F modifications, as well as phosphorothioate linkagesand tetraloop structures. A total of 96 different tetarloop constructs(eight modification patterns across twelve sequences) were tested inHeLa cells. Conversion of the 2′-O-methyl modification patterns of25/27mer DsiRNAs to tetraloop-possessing agents was performed in themanner shown in FIG. 8A. As shown in FIGS. 8D to 8J, a number of highlymodified tetraloop-possessing constructs were identified as potent inHeLa cell assays and were selected for scale-up synthesis. Thus,multiple sequences with multiple patterns were active as tetraloopconstructs. It was noted that M660/M594 and M660/M604 modificationpatterns were tolerated by most tested sequences. The followingconstructs were selected for scale-up and in vivo testing:LDHA-355-M650/M595; LDHA-355-M624/M596; LDHA-402-M650/M595;LDHA-718-M660/M604; LDHA-723-M624/M595; LDHA-723-M649/M595;LDHA-892-M660/M594; and LDHA-1360-M624/M595. Dose curve and stabilityanalyses are optionally performed upon such constructs.

The LDHA-723 M576/M491 tetraloop construct was also conjugated to GalNAcmoieties and tested for in vivo efficacy. As shown in FIG. 9A, thisagent was highly effective at knocking down the mouse Ldha gene inliver, under either of the two dosing regimens examined (single dose at10 mg/kg or 4×2.5 mg/kg dose). In particular, approximately 30% to 60%or greater knockdown of Ldha in liver was observed in all treatedanimals. Average levels of knockdown for single dose animals exceeded50% at three days post-administration. Thus, the tetraloop andGalNAc-conjugated form of LDHA-723 M576/M491 was confirmed to be highlyactive in liver tissue.

The tetraloop and GalNAc-conjugated form of LDHA-723 M576/M491 was alsoassessed for impact upon urine oxalate levels in PH1 model mice. In suchexperiments, C57BL/6 male mice were intravenously injected weekly withAgxt DsiRNA (in LNP 2185 formulation), to induce a PH1 model. Injectionof LDHA-targeting DsiRNA constructs was then performed by dosingschedules indicated by arrows in FIG. 9B (with intravenous injectionperformed for LNP-formulated DsiRNA LDHA-718-M24/M527 (DP2685P:DP2692G),while subcutaneous injection was performed for the tetraloop andGalNAc-conjugated form of LDHA-723 M576/M491). Urine samples werecollected manually at the indicated timepoints, and the tetraloop andGalNAc-conjugated form of LDHA-723 M576/M491 at 10 mg/kg was identifiedto have significantly reduced urine oxalate levels in the PH1 modelsystem mice.

The urine oxalate-reducing efficacy of the tetraloop andGalNAc-conjugated form of LDHA-723 M576/M491 appeared to bedose-dependent, as was further demonstrated in FIG. 9C. Specifically,varying doses of either LNP-formulated LDHA-718 or tetraloop andGalNAc-conjugated form of LDHA-723 M576/M491 were injected intravenouslyweekly into C57BL/6 male mice that had been pre-treated (and continuedto be treated) with Agxt DsiRNA (LNP 2185-formulated), and urine sampleswere obtained and assessed at seven days after the last dose. BothLNP-formulated LDHA-718 and the tetraloop and GalNAc-conjugated form ofLDHA-723 M576/M491 were observed to exhibit a dose-dependent effect onboth Ldha mRNA knockdown and reducing urine oxalate levels (FIG. 9C).Additional tetraloop and GalNAc-conjugated forms of LDHA-targetingDsiRNAs were also produced and tested, resulting in identification ofcertain tetraloop and GalNAc-conjugated forms of LDHA-targeting DsiRNAspossessing single dose IC₅₀ values of approximately 3.0 mg/kg (data notshown). Thus, highly active tetraloop and GalNAc-conjugated forms ofLDHA-targeting DsiRNAs were identified.

Example 7: LNP-Formulated LDHA-Targeting DsiRNA Knocked Down LDHA Levelsin Tumor Cells In Vivo

The effect of an LNP-formulated LDHA RNAi agent (specifically, theLDHA-718-M571/M550 25/27mer DsiRNA) in a Hep3B tumor model in nude micewas examined.

LDHA-718-M571/M550 was formulated in EnCore lipid nanoparticles(LNP2540) and tested in Hep3B tumor bearing mice. To generate a tumormodel, the nude mice were subcutaneously implanted with 5e6 Hep3B cellsand matrigel. When tumors reached an average size of 200 mm³, they weresorted into 3 groups (n=6), such that each group possessed similaraverage tumor size. These groups were then treated with either PBS,LNP2540/Control DsiRNA or with LNP2540/LDHA DsiRNA every day at 3mpk forthree days. After a four day break, the same treatment schedule wascontinued for another week. Tumor sizes were measured twice a week tomonitor the tumor growth during LDHA treatment. In addition tomonitoring tumor sizes, an additional set of mice (n=3) with tumors werealso kept in this study to monitor the target knockdown. 24 h after thefirst round of dosing, the tumors from satellite mice were collected todetermine LDHA mRNA knockdown (KD).

As shown in FIGS. 10A and 10B, LNP2540/LDHA-718-M571/M550 possessed highlevels of anti-tumor efficacy (TGI of 78%; FIG. 10A) and alsoproduced >75% knockdown of LDHA in Hep3B tumors of treated animals, onaverage (FIG. 10B), after a single round of dosing with theLNP/LDHA-718-M571/M550 DsiRNA.

Thus, an LNP-formulated LDHA DsiRNA was identified to be a robustinhibitor of liver tumor in vivo, and was also verified to have produceddramatic knockdown of LDHA in such liver tumor tissues.

Example 8: Liver-Specific Ldha DsiRNA Knockdown in Wild-Type Mice wasWell Tolerated

In view of the role of liver LDHA in processing plasma lactate, it waspossible that LDHA knockdown in liver would produce a deleteriousbuildup of plasma lactate levels. To examine whether LNP-formulatedLDHA-targeting DsiRNAs exhibited toxicity (e.g., as might be expected ifsignificant knockdown of LDHA in the liver caused plasma lactate toaccumulate) wild-type mice were administered the LDHA-718-M24/M527DsiRNA in LNP 2185, at a concentration of 3 mg/kg, weekly, viaintravenous injection. As is shown in FIG. 11, LNP-formulatedLDHA-targeting DsiRNAs were observed to have reduced the expression ofmRNA in liver tissue to less than 2% of control levels at the end of thestudy (FIG. 11, at left). Meanwhile, no elevation of plasma lactatelevels was observed in treated animals (FIG. 11, at center and right).Moreover, liver enzymes, blood chemistry, body weight and systemiclactic acid were all observed to be normal. Accordingly, LNP-formulatedLDHA-targeting DsiRNAs were well tolerated in vivo.

Example 9: DsiRNA Inhibition of LDHA—Secondary Screen

A selection of asymmetric DsiRNAs (e.g., 24 targeting Hs LDHA, aselection of which also target Mm lactate dehydrogenase) of the aboveexperiments (e.g., Examples 2-4) are also examined in a secondary assay(“Phase 2”). Specifically, the asymmetric DsiRNAs selected from thosetested above are assessed for inhibition of human lactate dehydrogenaseat 1 nM, 0.1 nM and 0.03 nM in the environment of human HeLa cells.These asymmetric DsiRNAs are then also assessed for inhibition of mouseLDHA at 1 nM, 0.1 nM and 0.03 nM in the environment of mouse B16-F10cells. Most asymmetric DsiRNAs are expected to reproducibly exhibitsignificant LDHA inhibitory efficacies at sub-nanomolar concentrationswhen assayed in the environment of HeLa cells. In addition, a selectnumber of asymmetric DsiRNAs are expected to be identified that possesssignificant mouse lactate dehydrogenase inhibitory efficacies atsub-nanomolar concentrations when assayed in the environment of mouseB16-F10 cells.

Example 10: Identification of Additional Modified Forms ofLDHA-Targeting DsiRNAs that Reduce Lactate Dehydrogenase Levels In Vitro

A selection (e.g., 12-24) of lactate dehydrogenase-targeting DsiRNAs ofthe above initial screen are prepared with 2′-O-methyl guide andpassenger strand modification patterns as described above; exemplarymodifications include “M107” modified passenger strands andabove-described guide strand modification patterns “M8”, “M17”, “M35”and “M48”). For each of the DsiRNA sequences, DsiRNAs possessing each ofthe four guide strand modification patterns M8, M17, M35 and M48 areassayed for LDHA inhibition in human HeLa cells at 1.0 nM, 0.1 nM and0.03 nM concentrations in the environment of the HeLa cells.Identification of a modification pattern that allows the DsiRNA toretain significant lactate dehydrogenase inhibitory efficacy in vitro istherefore achieved, with such highly active modified DsiRNA sequencespossessing modification patterns believed to be capable of stabilizingsuch DsiRNAs and/or reducing immunogenicity of such DsiRNAs whentherapeutically administered to a subject in vivo.

Example 11: Additional Forms of LDHA-Targeting DsiRNAs PossessingModifications of Both Guide and Passenger Strands

Additional LDHA-Targeting DsiRNAs of the above experiments are preparedwith 2′-O-methyl passenger strand and guide strand modificationpatterns, e.g., as represented above (including, e.g., passenger strandmodification patterns “SM14”, “SM24”, “SM107”, “SM250”, “SM251” and“SM252” and guide strand modification patterns “M48”, “M8” and “M17”).For each of the DsiRNA sequences, DsiRNAs possessing each of the sixpassenger strand modification patterns M14, M24, M107, M250, M251 andM252 and one preferred guide strand modification pattern (selected fromamong guide strand modification patterns M48, M8 and M17) are assayedfor lactate dehydrogenase inhibition in human HeLa cells at 1.0 nM, 0.1nM and 0.03 nM (30 picomolar) concentrations in the environment of theHeLa cells. Duplexes possessing extensive modification of both guide andpassenger strands are identified that still allow the DsiRNA to retainsignificant lactate dehydrogenase inhibitory efficacy in vitro. Highlyactive modified DsiRNA sequences so identified possess modificationpatterns believed to be capable of stabilizing such DsiRNAs and/orreducing immunogenicity of such DsiRNAs when therapeuticallyadministered to a subject in vivo.

Example 12: Indications

The present body of knowledge in lactate dehydrogenase researchindicates the need for methods to assay lactate dehydrogenase activityand for compounds that can regulate lactate dehydrogenase expression forresearch, diagnostic, and therapeutic use. As described herein, thenucleic acid molecules of the present invention can be used in assays todiagnose and/or monitor a disease state that has the potential to betreated by lactate dehydrogenase-targeting agents. In addition, thenucleic acid molecules can be used to treat such a disease state (e.g.,PH1).

Other therapeutic agents can be combined with or used in conjunctionwith the nucleic acid molecules (e.g. DsiRNA molecules) of the instantinvention. For example, for purpose of treating PH1, both anti-LDHA andanti-glycolate oxidase dsRNAs (e.g., DsiRNAs) can be combined to impedeoxalate production. Those skilled in the art will recognize that othercompounds and therapies used to treat the diseases and conditionsdescribed herein can be combined with the nucleic acid molecules of theinstant invention (e.g. siNA molecules) and are hence within the scopeof the instant invention. For example, for combination therapy, thenucleic acids of the invention can be prepared in one of at least twoways. First, the agents are physically combined in a preparation ofnucleic acid and other agent, such as a mixture of a nucleic acid of theinvention encapsulated in liposomes and other agent in a solution forintravenous administration, wherein both agents are present in atherapeutically effective concentration (e.g., the other agent insolution to deliver 1000-1250 mg/m2/day and liposome-associated nucleicacid of the invention in the same solution to deliver 0.1-100mg/kg/day). Alternatively, the agents are administered separately butsimultaneously or successively in their respective effective doses(e.g., 1000-1250 mg/m2/d other agent and 0.1 to 100 mg/kg/day nucleicacid of the invention).

Example 13: Serum Stability for DsiRNAs

Serum stability of DsiRNA agents is assessed via incubation of DsiRNAagents in 50% fetal bovine serum for various periods of time (up to 24h) at 37° C. Serum is extracted and the nucleic acids are separated on a20% non-denaturing PAGE and can be visualized with Gelstar stain.Relative levels of protection from nuclease degradation are assessed forDsiRNAs (optionally with and without modifications).

Example 14: Liver-Targeted LDHA Knockdown Effects in PH Model Mice

The etiology of chronic kidney stone formation and chronic kidneydisease is tested using largely liver-specific LDHA-targeting agents andformulations of the invention. Combined PH1, PH2 and PH3 models (e.g.,PH2/PH3, PH1/PH3, PH1/PH2 and/or PH1/PH2/PH3 models) are generated inlarge groups of mice, causing multiple simultaneous and interactingdisruptions of mono- and dicarboxylic acid metabolism. LNP-formulatedLDHA-targeting DsiRNAs and controls are tested in these animals, withthe expectation that LDHA knockdown will prove beneficial/corrective toeach model treated and examined.

Example 15: Diagnostic Uses

The DsiRNA molecules of the invention can be used in a variety ofdiagnostic applications, such as in the identification of moleculartargets (e.g., RNA) in a variety of applications, for example, inclinical, industrial, environmental, agricultural and/or researchsettings. Such diagnostic use of DsiRNA molecules involves utilizingreconstituted RNAi systems, for example, using cellular lysates orpartially purified cellular lysates. DsiRNA molecules of this inventioncan be used as diagnostic tools to examine genetic drift and mutationswithin diseased cells. The close relationship between DsiRNA activityand the structure of the target lactate dehydrogenase RNA allows thedetection of mutations in a region of the lactate dehydrogenasemolecule, which alters the base-pairing and three-dimensional structureof the target lactate dehydrogenase RNA. By using multiple DsiRNAmolecules described in this invention, one can map nucleotide changes,which are important to RNA structure and function in vitro, as well asin cells and tissues. Cleavage of target lactate dehydrogenase RNAs withDsiRNA molecules can be used to inhibit gene expression and define therole of specified gene products in the progression of PH1 or otherlactate dehydrogenase-associated disease or disorder. In this manner,other genetic targets can be defined as important mediators of thedisease. These experiments will lead to better treatment of the diseaseprogression by affording the possibility of combination therapies (e.g.,multiple DsiRNA molecules targeted to different genes, DsiRNA moleculescoupled with known small molecule inhibitors, or intermittent treatmentwith combinations of DsiRNA molecules and/or other chemical orbiological molecules). Other in vitro uses of DsiRNA molecules of thisinvention are well known in the art, and include detection of thepresence of RNAs associated with a disease or related condition. SuchRNA is detected by determining the presence of a cleavage product aftertreatment with a DsiRNA using standard methodologies, for example,fluorescence resonance emission transfer (FRET).

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein as presently representative ofpreferred embodiments are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications can be made to the invention disclosedherein without departing from the scope and spirit of the invention.Thus, such additional embodiments are within the scope of the presentinvention and the following claims. The present invention teaches oneskilled in the art to test various combinations and/or substitutions ofchemical modifications described herein toward generating nucleic acidconstructs with improved activity for mediating RNAi activity. Suchimproved activity can comprise improved stability, improvedbioavailability, and/or improved activation of cellular responsesmediating RNAi. Therefore, the specific embodiments described herein arenot limiting and one skilled in the art can readily appreciate thatspecific combinations of the modifications described herein can betested without undue experimentation toward identifying DsiRNA moleculeswith improved RNAi activity.

The invention illustratively described herein suitably can be practicedin the absence of any element or elements, limitation or limitationsthat are not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof”, and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments, optional features, modification and variation ofthe concepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the description and theappended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description.

The inventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A method for reducing expression of the lactate dehydrogenase (LDHA)gene in one or more tissues of a subject, comprising administering tothe subject an effective amount of a double stranded nucleic acid (dsNA)comprising a sense strand and an antisense strand, wherein the antisensestrand is 19-35 nucleotides in length, wherein the antisense strand iscomplementary to a target lactate dehydrogenase mRNA sequence as setforth in SEQ ID NO: 401 along at least 19 nucleotides of said antisensestrand length, and wherein the dsNA comprises one or more modifiednucleotides, thereby reducing expression of the LDHA gene in one or moretissues of the subject.
 2. The method of claim 1, wherein the subjecthas a lactate dehydrogenase knockdown treatable disease or disorder,wherein the disease or disorder is chronic kidney disease or pyruvatedehydrogenase complex deficiency.
 3. The method of claim 1, wherein thedisease or disorder is selected from the group consisting of PH1, PH2,PH3 and idiopathic hyperoxaluria.
 4. The method of claim 1, wherein thedsNA is administered in a lipid nanoparticle.
 5. The method of claim 1,wherein the one or more tissues comprises liver. 6-106. (canceled) 107.The method of claim 1, wherein the sense strand and antisense strandform a duplex such that the antisense strand comprises a two nucleotideoverhang at its 3′ end.
 108. The method of claim 1, wherein the dsNAcomprises a duplex of 19 to 25 base pairs in length.
 109. The method ofclaim 107, wherein the sense strand is 25 to 53 nucleotides in length.110. The method of claim 107, wherein the sense strand is 36 nucleotidesin length and/or wherein the antisense strand is 22 nucleotides inlength.
 111. The method of claim 1, wherein the sense strand and theantisense strand are each in the range of 21 to 23 nucleotides inlength.
 112. The method of claim 1, wherein the sense strand is 21nucleotides in length and the antisense strand is 23 nucleotides inlength.
 113. The method of claim 112, wherein the 3′ terminus of thesense strand and the 5′ terminus of the antisense strand form a bluntend.
 114. The method of claim 1, wherein the sense strand comprises atetraloop at its 3′ end.
 115. The method of claim 111, wherein the sensestrand comprises a tetraloop at its 3′ end.
 116. The method of claim114, wherein the tetraloop comprises a single stranded loop having asequence of GAAA.
 117. The method of claim 1, wherein the dsNA comprisesat least one phosphorothioate linkage.
 118. The method of claim 116,wherein the dsNA comprises at least one phosphorothioate linkage. 119.The method of claim 1, wherein the one or more modified nucleotidescontains a 2′ modification.
 120. The method of claim 119, wherein theone or more modified nucleotides are selected from a 2′-O-methylnucleotide and a 2′-fluoro nucleotide.
 121. The method of claim 120,wherein the dsNA comprises at least one 2′-fluoro nucleotide and atleast one 2′-O-methyl nucleotide.
 122. The method of claim 1, whereinthe dsNA is attached to a moiety selected from the group consisting of aGalNAc moiety, a cholesterol moiety, and a cholesterol targeting ligand.123. The method of claim 120, wherein the dsNA is attached to a GalNAcmoiety.
 124. The method of claim 123, wherein the dsNA is administeredin a pharmaceutical composition, wherein the pharmaceutical compositionfurther comprises a pharmaceutically acceptable carrier.
 125. A methodfor reducing expression of the lactate dehydrogenase (LDHA) gene in oneor more tissues of a subject, comprising administering to the subject aneffective amount of a nucleic acid comprising an oligonucleotide strandof 19-35 nucleotides in length, wherein said oligonucleotide strand iscomplementary to a target lactate dehydrogenase mRNA sequence as setforth in SEQ ID NO: 401 along at least 19 nucleotides of saidoligonucleotide strand length, and wherein the nucleic acid comprisesone or more modified nucleotides, thereby reducing expression of theLDHA gene in one or more tissues of the subject.
 126. A method forreducing expression of the lactate dehydrogenase (LDHA) gene in amammalian cell comprising administering to the mammalian cell aneffective amount of a nucleic acid comprising an oligonucleotide strandof 19-35 nucleotides in length, wherein said oligonucleotide strand iscomplementary to a target lactate dehydrogenase mRNA sequence as setforth in SEQ ID NO: 401 along at least 19 nucleotides of saidoligonucleotide strand length, and wherein the nucleic acid comprisesone or more modified nucleotides, in an amount sufficient to reduceexpression of a target lactate dehydrogenase mRNA in said cell, therebyreducing expression of the LDHA gene in the mammalian cell.
 127. Themethod of claim 125, wherein the nucleic acid is in a pharmaceuticalcomposition, wherein the pharmaceutical composition further comprises apharmaceutically acceptable carrier.
 128. A method of reducingexpression of the lactate dehydrogenase gene (LDHA) in one or moretissues of a subject comprising administering to the subject a doublestranded nucleic acid (dsNA) comprising a sense strand and an antisensestrand, wherein the antisense strand is 19-35 nucleotides in length,wherein the antisense strand is complementary to a target lactatedehydrogenase mRNA sequence as set forth in SEQ ID NO: 401 along atleast 19 nucleotides of said antisense strand length, wherein thecomplementary region of the antisense strand contains between one andfour mismatched nucleotide residues relative to SEQ ID NO: 401, andwherein the dsNA comprises one or more modified nucleotides, therebyreducing expression of the LDHA gene in one or more tissues of thesubject.
 129. The method of claim 128, wherein the complementary regionof the antisense strand contains three, two, or one mismatchednucleotide residues relative to SEQ ID NO:
 401. 130. The method of claim128, wherein the sense strand and antisense strand form a duplex suchthat the antisense strand comprises a two nucleotide overhang at its 3′end.
 131. The method of claim 128, wherein the dsNA comprises a duplexof 19 to 25 base pairs in length.
 132. The method of claim 130, whereinthe sense strand is 25 to 53 nucleotides in length.
 133. The method ofclaim 130, wherein the sense strand is 36 nucleotides in length and/orwherein the antisense strand is 22 nucleotides in length.
 134. Themethod of claim 128, wherein the sense strand and the antisense strandare each in the range of 21 to 23 nucleotides in length.
 135. The methodof claim 128, wherein the sense strand is 21 nucleotides in length andthe antisense strand is 23 nucleotides in length.
 136. The method ofclaim 135, wherein the 3′ terminus of the sense strand and the 5′terminus of the antisense strand form a blunt end.
 137. The method ofclaim 128, wherein the sense strand comprises a tetraloop at its 3′ end.138. The method of claim 134, wherein the sense strand comprises atetraloop at its 3′ end.
 139. The method of claim 137, wherein thetetraloop comprises a single stranded loop having a sequence of GAAA.140. The method of claim 3, wherein the disease or disorder is PH1.